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1. Enhanced Efficiency of flySAM by Optimization of sgRNA Parameters in Drosophila

Author

Xingjie Ren, Jinchao Yu, Ping Peng, Yu Jia, Yuhao Qiu, Yutong Li, Qingfei Liu, Da Shen, Ruibao Zhu, Xinyi Lu, Jian-Quan Ni, Yuting Han, Qinyun Che, Zhao Wang, Decai Mao, Lu-Ping Liu, and Jin Sun

Subjects
flysam, Computational biology, Investigations, QH426-470, Positive correlation, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, position effect, Genetics, Animals, sgrna, Promoter Regions, Genetic, Molecular Biology, Genetics (clinical), 030304 developmental biology, Subgenomic mRNA, 0303 health sciences, Base Composition, biology, gc content, biology.organism_classification, Position effect, Drosophila melanogaster, chemistry, Coding strand, Drosophila, dna strand, CRISPR-Cas Systems, Transcription Initiation Site, 030217 neurology & neurosurgery, GC-content, DNA, RNA, Guide, Kinetoplastida
Abstract

The flySAM/CRISPRa system has recently emerged as a powerful tool for gain-of-function studies in Drosophila melanogaster. This system includes Gal4/UAS-driven dCas9 activators and U6 promoter-controlled sgRNA. Having established dCas9 activators superior to other combinations, to further enhance the efficiency of the targeting activators we systematically optimized the parameters of the sgRNA. Interestingly, the most efficient sgRNAs were found to accumulate in the region from -150bp to -450bp upstream of the transcription start site (TSS), and the activation efficiency showed a strong positive correlation with the GC content of the sgRNA targeting sequence. In addition, the target region is dominant to the GC content, as sgRNAs targeting areas beyond -600bp from the TSS lose efficiency even when containing 75% GC. Surprisingly, when comparing the activities of sgRNAs targeting to either DNA strand, sgRNAs targeting to the non-template strand outperform those complementary to the template strand, both in cells and in vivo. In summary, we define criteria for sgRNA design which will greatly facilitate the application of CRISPRa in gain-of-function studies.

Published
2020
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2. A novel oncotherapy strategy: Direct thrombin inhibitors suppress progression, dissemination and spontaneous metastasis in non-small cell lung cancer

Author

Zhihuang Hu, Yixin Ma, Jinchao Yu, Mengfang Wu, Zhang Yanling, Yu Min, Yaran Li, Huijie Wang, Mo Wei, Tianfa Wang, Di Chen, Zhao Bing, Tianyu Li, and Qi Wang

Subjects
0301 basic medicine, Lung Neoplasms, Angiogenesis, Antineoplastic Agents, Malignancy, Antithrombins, Metastasis, 03 medical and health sciences, Mice, 0302 clinical medicine, Thrombin, Fibrinolytic Agents, Carcinoma, Non-Small-Cell Lung, medicine, Animals, Neoplasm Metastasis, Lung cancer, Pharmacology, business.industry, Interleukin-6, NF-kappa B, Cancer, Hirudins, medicine.disease, Primary tumor, 030104 developmental biology, Matrix Metalloproteinase 9, Tumor progression, Direct thrombin inhibitor, Cancer research, business, 030217 neurology & neurosurgery, Discovery and development of direct thrombin inhibitors, medicine.drug
Abstract

Background and purpose Cancer cachexia and cancer-associated thrombosis are potentially fatal outcomes of advanced cancer. Nevertheless, thrombin expression in non-small cell lung cancer (NSCLC) primary tumour tissues and the association between prognosis of NSCLC patients remain largely unknown. Experimental approach Clinical pathological analysis was performed to determine the relationship between thrombin and tumour progression. Effects of r-hirudin and direct thrombin inhibitor peptide (DTIP) on cancer progression were evaluated. Western blotting, immunohistochemistry, and immunofluorescence were used to explore the inhibition mechanism of r-hirudin and DTIP. The therapeutic effect of the combination of DTIP and chemotherapy was determined. Key results Thrombin expression in NSCLC tissues was closely related to clinicopathological features and the prognosis of patients. Thrombin deficiency inhibited tumour progression. The novel thrombin inhibitors, r-hirudin and DTIP, inhibited cell invasion and metastasis in vitro. They inhibited tumour growth and metastasis in orthotopic lung cancer model, inhibited cell invasion, and prolonged survival after injection of tumour cells via the tail vein. They also inhibited angiogenesis and spontaneous metastases from subcutaneously inoculated tumours. The promotion by thrombin of invasion and metastasis was abolished in PAR-1-deficient NSCLC cells. r-hirudin and DTIP inhibited tumour progression through the thrombin-PAR-1-mediated RhoA and NF-κB signalling cascades via inhibiting MMP9 and IL6 expression. DTIP potentiated chemotherapy-induced growth and metastatic inhibition and inhibited chemotherapy-induced resistance in mice. Conclusions and implications Thrombin makes a substantial contribution, together with PAR-1, to NSCLC malignancy. The anti-coagulants, r-hirudin and DTIP, could be used in anti-tumour therapy and a combination of DTIP and chemotherapy might improve therapeutic effects.

Published
2021

3. Related Factors of Asymmetrical Vein Sign in Acute Middle Cerebral Artery Stroke and Correlation with Clinical Outcome

Author

Guangbin Wang, Shanshan Wang, Liming Wang, Zhenzhi Li, and Jinchao Yu

Subjects
Adult, Male, medicine.medical_specialty, animal structures, viruses, Severity of Illness Index, 030218 nuclear medicine & medical imaging, Correlation, 03 medical and health sciences, 0302 clinical medicine, Modified Rankin Scale, medicine.artery, Internal medicine, Odds Ratio, Humans, Medicine, cardiovascular diseases, skin and connective tissue diseases, Vein, Stroke, Aged, Aged, 80 and over, Related factors, medicine.diagnostic_test, business.industry, Rehabilitation, Brain, virus diseases, Infarction, Middle Cerebral Artery, Magnetic resonance imaging, Middle Aged, Prognosis, Cortical Vein, medicine.disease, Magnetic Resonance Imaging, Cerebral Angiography, Surgery, Logistic Models, medicine.anatomical_structure, Multivariate Analysis, Middle cerebral artery, Cardiology, Female, Neurology (clinical), Cardiology and Cardiovascular Medicine, business, 030217 neurology & neurosurgery
Abstract

The aim of our study was to analyze the related factors of asymmetrical cortical vein sign (ACVS) and asymmetrical medullary vein sign (AMVS) on susceptibility-weighted imaging (SWI) in patients with acute middle cerebral artery (MCA) stroke and whether their presence can be used as an independent predictor for clinical outcome.According to the presence of ACVS and AMVS on SWI, 124 patients with acute MCA stroke within 3 days were divided into several different groups. In addition, those patients were also divided into good and poor outcome group by using the modified Rankin Scale at 3 months after stroke. We investigated respectively the differences in magnetic resonance imaging findings and the clinical data among those different groups.The ACVS was demonstrated in 90 of 124 patients. Of the 90 patients, 47 were accompanied with the AMVS. The rest of 34 patients showed no ACVS and AMVS. The infarct size and MCA status showed significant differences among the ACVS+, AMVS+ group; ACVS+, AMVS- group; and ACVS-, AMVS- group (all P .001). Moreover, the ACVS, AMVS, and MCA occlusion were more common in the poor outcome group (all P .001). In the multivariate logistic regression, AMVS (P = .027; odds ratio, 2.37; 95% confidence interval, 1.23-8.73) was associated with poor outcome.The ACVS and AMVS were correlated to the status of MCA steno-occlusion and infarct size, whereas the AMVS was proved to be independently related to the stroke severity and poor outcome rather than the ACVS.

Published
2017
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4. The usefulness of narrow-band imaging for the diagnosis and treatment of vocal fold leukoplakia

Author

Fan Zhang, Jun Shao, Shimin Li, Fang Huang, Jinchao Yu, and Changding He

Subjects
Adult, Male, medicine.medical_specialty, Pathology, Hyperkeratosis, Gastroenterology, Narrow Band Imaging, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, medicine, Carcinoma, Humans, 030223 otorhinolaryngology, Parakeratosis, Laryngeal Neoplasms, Aged, Moderate Dysplasia, Leukoplakia, Aged, 80 and over, Narrow-band imaging, business.industry, Carcinoma in situ, General Medicine, Middle Aged, medicine.disease, Otorhinolaryngology, Dysplasia, 030220 oncology & carcinogenesis, Female, medicine.symptom, business
Abstract

Objective: This research was aimed to explore the efficacy of narrow-band imaging (NBI) on distinguishing the degree of dysplasia of vocal fold leukoplakia.Methods: Patients were examined by flexible endoscopy, under white light endoscopy (WLE) and NBI. 78 lesions were divided into two groups according to the NBI classification. Group 1: non-dysplasia (ND), including squamous hyperplasia with hyperkeratosis or parakeratosis; Group 2: squamous hyperplasia with mild or moderate dysplasia (MD) or severe dysplasia (SD), or carcinoma in situ (CIS).Results: The diagnostic accuracy of NBI for Group 1 and Group 2 was 69.70% (23/33) and 95.56% (43/45), respectively, and the kappa index was 0.711 and a p value

Published
2017
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5. Detection and Treatment of Persistent Mullerian Duct Syndrome With Transverse Testicular Ectopia

Author

Shengjun Ma, Liming Wang, Zhenzhi Li, and Jinchao Yu

Subjects
Male, medicine.medical_specialty, Urology, 030232 urology & nephrology, 03 medical and health sciences, 0302 clinical medicine, Testis, medicine, Humans, Laparoscopic resection, Disorder of Sex Development, 46,XY, medicine.diagnostic_test, Ectopic testis, business.industry, Magnetic resonance imaging, Middle Aged, medicine.disease, body regions, Inguinal hernia, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Persistent Müllerian duct syndrome, Indirect inguinal hernia, Testicular ectopia, Radiology, business, Duct (anatomy)
Abstract

The coexistence of persistent Mullerian duct syndrome (PMDS) with transverse testicular ectopia (TTE) is extremely rare. Due to a lack of distinctive clinical features in the early stages, PMDS coexists with TTE is usuallydiagnosed when patients are examined for other diseases,including cryptorchidism and inguinal hernia. We present a case of a 51-year-old man who presented with a recurrent left indirect inguinal hernia for 2 years and right congenital cryptorchidism. The patient was diagnosed as PMDS with TTE by preoperative magnetic resonance imaging and underwent laparoscopic resection of the right transverse ectopic testis and Mullerian duct residues.

Published
2020
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6. Next-generation drug repurposing using human genetics and network biology

Author

Philippe Rinaudo, Serguei Nabirotchkin, Jinchao Yu, Alex E. Peluffo, Rodolphe Hajj, and Daniel Cohen

Subjects
0301 basic medicine, Computer science, Context (language use), 030226 pharmacology & pharmacy, Machine Learning, 03 medical and health sciences, 0302 clinical medicine, Drug Discovery, Animals, Humans, Gene Regulatory Networks, Pharmacology, business.industry, Drug discovery, Drug Repositioning, Human Genetics, Genetic Therapy, Data science, Human genetics, Drug repositioning, 030104 developmental biology, Identification (biology), Lower cost, Personalized medicine, business, Biological network, Genome-Wide Association Study
Abstract

Drug repurposing has attracted increased attention, especially in the context of drug discovery rates that remain too low despite a recent wave of approvals for biological therapeutics (e.g. gene therapy). These new biological entities-based treatments have high costs that are difficult to justify for small markets that include rare diseases. Drug repurposing, involving the identification of single or combinations of existing drugs based on human genetics data and network biology approaches represents a next-generation approach that has the potential to increase the speed of drug discovery at a lower cost. This Pharmacological Perspective reviews progress and perspectives in combining human genetics, especially genome-wide association studies, with network biology to drive drug repurposing for rare and common diseases with monogenic or polygenic etiologies. Also, highlighted here are important features of this next generation approach to drug repurposing, which can be combined with machine learning methods to meet the challenges of personalized medicine.

Published
2019

7. Large-scale transgenicDrosophilaresource collections for loss- and gain-of-function studies

Author

Xia Wang, Jonathan Zirin, Ruibao Zhu, Ping Peng, Rong Tao, Shu Kondo, Dong Yan, Kuniaki Saito, Liz Perkins, Henna Ragoowansi, Jin Sun, Ethan Fenton, Ryan Colbeth, Benjamin Scott Ewen-Campen, Senait Efrem, Annette L. Parks, Limmond Ayisi, Sara VanNest, Donghui Yang-Zhou, Yuhao Qiu, Cooper Cavers, Norbert Perrimon, Aram Comjean, Jian-Quan Ni, Stephanie E. Mohr, Eric Vogt, Yanhui Hu, Jinchao Yu, Lu-Ping Liu, Da Shen, Christians Villalta, and Yu Jia

Subjects
Computational biology, Investigations, Biology, Genome engineering, Animals, Genetically Modified, 03 medical and health sciences, 0302 clinical medicine, Loss of Function Mutation, RNA interference, Databases, Genetic, Genetics, Animals, CRISPR, Coding region, Gene, 030304 developmental biology, Regulation of gene expression, 0303 health sciences, Cas9, fungi, biology.organism_classification, Drosophila melanogaster, Gain of Function Mutation, ComputingMethodologies_DOCUMENTANDTEXTPROCESSING, ComputingMethodologies_GENERAL, CRISPR-Cas Systems, Genetic Engineering, human activities, Functional genomics, 030217 neurology & neurosurgery
Abstract

The Transgenic RNAi Project (TRiP), a Drosophila melanogaster functional genomics platform at Harvard Medical School, was initiated in 2008 to generate and distribute a genome-scale collection of RNA interference (RNAi) fly stocks. To date, it has generated >15,000 RNAi fly stocks. As this covers most Drosophila genes, we have largely transitioned to development of new resources based on CRISPR technology. Here, we present an update on our libraries of publicly available RNAi and CRISPR fly stocks, and focus on the TRiP-CRISPR overexpression (TRiP-OE) and TRiP-CRISPR knockout (TRiP-KO) collections. TRiP-OE stocks express single guide RNAs targeting upstream of a gene transcription start site. Gene activation is triggered by coexpression of catalytically dead Cas9 fused to an activator domain, either VP64-p65-Rta or Synergistic Activation Mediator. TRiP-KO stocks express one or two single guide RNAs targeting the coding sequence of a gene or genes. Cutting is triggered by coexpression of Cas9, allowing for generation of indels in both germline and somatic tissue. To date, we have generated >5000 TRiP-OE or TRiP-KO stocks for the community. These resources provide versatile, transformative tools for gene activation, gene repression, and genome engineering.

Published
2019
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8. The utility of narrow band imaging in endoscopic diagnosis of laryngopharyngeal reflux

Author

Jinchao Yu, Fang Huang, Changding He, and Jun Shao

Subjects
Adult, Male, medicine.medical_specialty, urologic and male genital diseases, Sensitivity and Specificity, Severity of Illness Index, 03 medical and health sciences, Laryngopharyngeal reflux, Narrow Band Imaging, Young Adult, 0302 clinical medicine, Vascularity, immune system diseases, Reference Values, Throat, Surveys and Questionnaires, medicine, Laryngopharyngeal Reflux, Humans, In patient, skin and connective tissue diseases, 030223 otorhinolaryngology, Aged, Retrospective Studies, Observer Variation, Contact ulcers, Narrow-band imaging, Laryngoscopy, business.industry, Reflux, Middle Aged, Control subjects, medicine.disease, medicine.anatomical_structure, Otorhinolaryngology, 030220 oncology & carcinogenesis, Case-Control Studies, Female, Radiology, medicine.symptom, business
Abstract

This study assessed the utility of narrow band imaging (NBI) in patients with symptoms of laryngopharyngeal reflux (LPR) and tried to quantitatively evaluate the signs found under the NBI Laryngoscope.Patients with and without LPR symptoms completed reflux symptom index (RSI) questionnaires prior to enrolment. The throat was examined by standard white light endoscopy followed by NBI. LPR status was determined using the reflux finding score and the RSI. Laryngoscope images and videos from 70 subjects with LPR and 70 control subjects without LPR were obtained. Features seen only by NBI were compared between the two groups. Then the RGB values of the throat mucosa of the two groups were measured by Photoshop software, and finally statistical analysis was performed.In total, 140 patients were eligible for final analysis (LPR group mean age = 50.0, 47 males; control group mean age = 44.8, 45 males). A significantly higher proportion of patients with LPR had increased vascularity, green spots, contact ulcers and granulomas. Of these, increased vascularity and green spots can only be found under NBI, and the prevalence rates in the LPR group were found to be 92.8% and 88.6% (P 0.05), respectively. In the control group, the prevalence rates of increased vascularity and green spots were 21.4% and 7.1%, respectively (P 0.05). The RGB value of the LPR group was generally higher than that of the control group. The difference is statistically significant (P 0.05).LPR presents vascularity and green spots with high specificity and sensitivity under NBI which can play a role in the auxiliary diagnosis of LPR.

Published
2019

9. RhTyrRS (Y341A), a novel human tyrosyl-tRNA synthetase mutant, stimulates thrombopoiesis through activation of the VEGF-R II/NF-κB pathway

Author

Jinchao Yu, Yuhao Ye, Yanling Zhang, Min Yu, Qiang Yu, Jianxin Gu, Yun Shi, Wei Mo, Bing Zhao, and Yaran Li

Subjects
0301 basic medicine, Male, Mutant, Vascular Cell Adhesion Molecule-1, medicine.disease_cause, Biochemistry, Thrombopoiesis, Rats, Sprague-Dawley, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Megakaryocyte, Downregulation and upregulation, Tyrosine-tRNA Ligase, medicine, Animals, Humans, Platelet, Phosphorylation, Cells, Cultured, Pharmacology, Mutation, NF-kappa B, NF-κB, Vascular Endothelial Growth Factor Receptor-2, Rats, 030104 developmental biology, medicine.anatomical_structure, Platelet transfusion, chemistry, 030220 oncology & carcinogenesis, Cancer research, Female, Signal Transduction
Abstract

Bacground and purpose Tumor chemotherapy and radiotherapy induces hematopoietic cell damage, resulting in thrombocytopenia. Conventional platelet transfusion strategies or drug therapies are used to treat thrombocytopenia. However, these therapies may result in a several side effects, including heightened susceptibility to infectious diseases and the formation of anti-TPO-antibodies. Therefore, a more secure strategy should be explored to overcome and compensate for the shortcomings of conventional strategies. Experimental approach Effects of rhTyrRS(Y341A) on the expression of VCAM-1 on the surface of HUVECs were determined by analysing mRNA expression, promoter activity, protein expression. The molecular mechanisms of the effects of rhTyrRS(Y341A) on the expression of VCAM-1 on the surface of HUVECs were investigated by determining the activation of VEGF-R II/NF-κB pathway. Key results Our results provide evidence that rhTyrRS (Y341A) activates NF-κB to upregulate VCAM-1 in a VEGF-R II/NF-κB pathway-dependent, resulting in megakaryocyte adhering to PVECs to induce platelet production. Conclusions This study suggested that rhTyrRS (Y341A), a novel human tyrosyl-tRNA synthetase mutation, increased the platelet count under normal conditions. Further more, we confirmed that an NF-κB-mediated mechanism is involved in rhTyrRS (Y341A)-induced thrombopoiesis, which involves its interaction with VEGF-R II.

Published
2019

10. Septin 9 has two polybasic domains critical to septin filament assembly and golgi integrity

Author

Stéphane Bressanelli, Richard Charles Garratt, Raphael Guerois, Christian Poüs, Ama Gassama-Diagne, Jinchao Yu, Bruno Goud, Abdou Rachid Thiam, Amanda Souza Camara, Didier Samuel, Mohyeddine Omrane, Nassima Benzoubir, Cyntia Taveneau, Thibault Tubiana, Physiopathologie et traitement des maladies du foie, Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Laboratoire de Physique Théorique de l'ENS [École Normale Supérieure] (LPTENS), Fédération de recherche du Département de physique de l'Ecole Normale Supérieure - ENS Paris (FRDPENS), École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Universidade de São Paulo = University of São Paulo (USP), Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Biologie Cellulaire et Cancer, Institut Curie [Paris]-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Physique Théorique de l'ENS (LPTENS), Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Universidade de São Paulo (USP), and CCSD, Accord Elsevier

Subjects
0301 basic medicine, [SDV]Life Sciences [q-bio], Membrane Architecture, 02 engineering and technology, macromolecular substances, Septin, 01 natural sciences, Article, Protein filament, 03 medical and health sciences, symbols.namesake, Organelle, 0103 physical sciences, lcsh:Science, POLIMERIZAÇÃO, 030304 developmental biology, 0303 health sciences, Multidisciplinary, Functional Aspects of Cell Biology, 010304 chemical physics, Molecular Interaction, Chemistry, fungi, virus diseases, Cell Biology, Golgi apparatus, biochemical phenomena, metabolism, and nutrition, 021001 nanoscience & nanotechnology, Protein enrichment, Cell biology, [SDV] Life Sciences [q-bio], 030104 developmental biology, Membrane, Membrane remodeling, symbols, lcsh:Q, biological phenomena, cell phenomena, and immunity, 0210 nano-technology
Abstract

Summary Septins are GTP-binding proteins involved in several membrane remodeling mechanisms. They associate with membranes, presumably using a polybasic domain (PB1) that interacts with phosphoinositides (PIs). Membrane-bound septins assemble into microscopic structures that regulate membrane shape. How septins interact with PIs and then assemble and shape membranes is poorly understood. Here, we found that septin 9 has a second polybasic domain (PB2) conserved in the human septin family. Similar to PB1, PB2 binds specifically to PIs, and both domains are critical for septin filament formation. However, septin 9 membrane association is not dependent on these PB domains, but on putative PB-adjacent amphipathic helices. The presence of PB domains guarantees protein enrichment in PI-contained membranes, which is critical for PI-enriched organelles. In particular, we found that septin 9 PB domains control the assembly and functionality of the Golgi apparatus. Our findings offer further insight into the role of septins in organelle morphology., Graphical Abstract, Highlights • Two polybasic domains mediate septin 9 interactions with PIs • Human septins have amphipathic helices suitable for membrane binding • Septin 9 polybasic domains mediate the formation of septin higher-order structures • The mutation or depletion of septin polybasic domains induces Golgi fragmentation, Membrane Architecture; Molecular Interaction; Cell Biology; Functional Aspects of Cell Biology

Published
2019
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11. Lessons from (co-)evolution in the docking of proteins and peptides for CAPRI Rounds 28-35

Author

Raphael Guerois, Jinchao Yu, Jessica Andreani, and Françoise Ochsenbein

Subjects
0301 basic medicine, business.industry, Biology, Machine learning, computer.software_genre, Biochemistry, 03 medical and health sciences, 030104 developmental biology, Protein–ligand docking, Critical Assessment of Prediction of Interactions, Structural Biology, Docking (molecular), Macromolecular docking, Artificial intelligence, Evolutionary information, business, Molecular Biology, computer, Simulation
Abstract

Computational protein-protein docking is of great importance for understanding protein interactions at the structural level. CAPRI (Critical Assessment of PRediction of Interactions) experiments provide the protein docking community with a unique opportunity to blindly test methods based on real-life cases and help accelerate methodology development. For CAPRI rounds 28-35, we used an automatic docking pipeline integrating the coarse-grained co-evolution-based potential InterEvScore. This score was developed to exploit the information contained in the multiple sequence alignments of binding partners and selectively recognize co-evolved interfaces. Together with Zdock/Frodock for rigid-body docking, SOAP-PP for atomic potential and Rosetta applications for structural refinement, this pipeline reached high performance on a majority of targets. For protein-peptide docking and interfacial water position predictions, we also explored different means of taking evolutionary information into account. Overall, our group ranked 1st by correctly predicting 10 targets, composed of 1 High, 7 Medium and 2 Acceptable predictions. Excellent and Outstanding levels of accuracy were reached for each of the two water prediction targets, respectively. Altogether, in 15 out of 18 targets in total, evolutionary information, either through co-evolution or conservation analyses, could provide key constraints to guide modeling towards the most likely assemblies. These results open promising perspectives regarding the way evolutionary information can be valuable to improve docking prediction accuracy. This article is protected by copyright. All rights reserved.

Published
2016
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12. Disentangling the molecular determinants for Cenp-F localization to nuclear pores and kinetochores

Author

Alessandro Berto, Jinchao Yu, Chiara Bertipaglia, Valérie Doye, Julien Dumont, Raphael Guerois, Françoise Ochsenbein, Richard B. Vallee, Stéphanie Morchoisne-Bolhy, Institut de Biologie Intégrative de la Cellule (I2BC), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Saclay, Assemblage moléculaire et intégrité du génome (AMIG), Département Biochimie, Biophysique et Biologie Structurale (B3S), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Saclay-Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Saclay-Institut de Biologie Intégrative de la Cellule (I2BC), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Saclay-Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Saclay, Institut Jacques Monod (IJM (UMR_7592)), Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Deptartment of Pathology and Cell Biology, Columbia University [New York], Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Intégrative de la Cellule (I2BC), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)

Subjects
0301 basic medicine, Leucine zipper, Chromosomal Proteins, Non-Histone, Nuclear Envelope, [SDV]Life Sciences [q-bio], Scientific Report, BUB1, Mitosis, Cell Cycle Proteins, macromolecular substances, Protein Serine-Threonine Kinases, Biochemistry, in silico modeling, Minor Histocompatibility Antigens, 03 medical and health sciences, 0302 clinical medicine, Prophase, Genetics, Humans, Nuclear pore, Binding site, Molecular Biology, Chemistry, Kinetochore, mitosin, Microfilament Proteins, Nuclear Proteins, kinetochores, Cenp-F, Cell cycle, 3. Good health, Cell biology, Nuclear Pore Complex Proteins, 030104 developmental biology, nuclear pore, 030217 neurology & neurosurgery, HeLa Cells, Protein Binding
Abstract

International audience; Cenp-F is a multifaceted protein implicated in cancer and developmental pathologies. The Cenp-F C-terminal region contains overlapping binding sites for numerous proteins that contribute to its functions throughout the cell cycle. Here, we focus on the nuclear pore protein Nup133 that interacts with Cenp-F both at nuclear pores in prophase and at kinetochores in mitosis, and on the kinase Bub1, known to contribute to Cenp-F targeting to kinetochores. By combining in silico structural modeling and yeast two-hybrid assays, we generate an interaction model between a conserved helix within the Nup133 β-propeller and a short leucine zipper-containing dimeric segment of Cenp-F. We thereby create mutants affecting the Nup133/Cenp-F interface and show that they prevent Cenp-F localization to the nuclear envelope, but not to kinetochores. Conversely, a point mutation within an adjacent leucine zipper affecting the kinetochore targeting of Cenp-F KT-core domain impairs its interaction with Bub1, but not with Nup133, identifying Bub1 as the direct KT-core binding partner of Cenp-F. Finally, we show that Cenp-E redundantly contributes together with Bub1 to the recruitment of Cenp-F to kinetochores.

Published
2018
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13. XLF and APLF bind Ku80 at two remote sites to ensure DNA repair by non-homologous end joining

Author

Eric Le Cam, Imre Berger, Sonia Baconnais, Patrick Calsou, Yandong Yin, Emeline Barbet-Massin, Pierre Legrand, Philippe Frit, Clément Nemoz, Jinchao Yu, Audrey Comte, Christine Delteil, Amandine Gontier, Aurelien Pitois, Satish K. Tadi, Jean-Baptiste Charbonnier, Raphael Guerois, Pascal Drevet, Nadia Barboule, Virginie Ropars, Mauro Modesti, Eli Rothenberg, Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Enveloppe Nucléaire, Télomères et Réparation de l’ADN (INTGEN), Département Biochimie, Biophysique et Biologie Structurale (B3S), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Institut de pharmacologie et de biologie structurale (IPBS), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Assemblage moléculaire et intégrité du génome (AMIG), Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Biologie Cellulaire et Moléculaire du Contrôle de la Prolifération (LBCMCP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre de Biologie Intégrative (CBI), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Synchrotron SOLEIL (SSOLEIL), Centre National de la Recherche Scientifique (CNRS), Signalisation, noyaux et innovations en cancérologie (UMR8126), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Centre National de la Recherche Scientifique (CNRS), Biological Solid-State NMR Methods - Méthodes de RMN à l'état solide en biologie, Institut des Sciences Analytiques (ISA), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), European Molecular Biology Laboratory [Grenoble] (EMBL), Institut Gustave Roussy (IGR), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Intégrative de la Cellule (I2BC), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre de Biologie Intégrative (CBI), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Aix Marseille Université (AMU), Institut de Chimie du CNRS (INC)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)

Subjects
Models, Molecular, 0301 basic medicine, DNA End-Joining Repair, Ku80, DNA repair, [SDV]Life Sciences [q-bio], Protein domain, BrisSynBio, Crystallography, X-Ray, DNA-binding protein, Article, 03 medical and health sciences, Protein Domains, Structural Biology, DNA-(Apurinic or Apyrimidinic Site) Lyase, Humans, Binding site, Poly-ADP-Ribose Binding Proteins, Ku Autoantigen, Molecular Biology, Conserved Sequence, ComputingMilieux_MISCELLANEOUS, 030102 biochemistry & molecular biology, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], Chemistry, Bristol BioDesign Institute, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, DNA repair protein XRCC4, Cell biology, DNA-Binding Proteins, Non-homologous end joining, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM], DNA Repair Enzymes, 030104 developmental biology, Synthetic Biology
Abstract

International audience; The Ku70-Ku80 (Ku) heterodimer binds rapidly and tightly to the ends of DNA double-strand breaks and recruits factors of the non-homologous end-joining (NHEJ) repair pathway through molecular interactions that remain unclear. We have determined crystal structures of the Ku-binding motifs (KBM) of the NHEJ proteins APLF (A-KBM) and XLF (X-KBM) bound to a Ku-DNA complex. The two KBM motifs bind remote sites of the Ku80 alpha/beta domain. The X-KBM occupies an internal pocket formed by an unprecedented large outward rotation of the Ku80 alpha/beta domain. We observe independent recruitment of the APLF-interacting protein XRCC4 and of XLF to laser-irradiated sites via binding of A- and X-KBMs, respectively, to Ku80. Finally, we show that mutation of the X-KBM and A-KBM binding sites in Ku80 compromises both the efficiency and accuracy of end joining and cellular radiosensitivity. A- and X-KBMs may represent two initial anchor points to build the intricate interaction network required for NHEJ.

Published
2018
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14. Direct interaction between exocyst and Wave complexes promotes cell protrusions and motility

Author

Maud Hertzog, Amel Sadou-Dubourgnoux, Jacques Camonis, Alexis Gautreau, Raphael Guerois, Giulia Zago, Marco Biondini, Perrine Paul-Gilloteaux, François Waharte, Melis D Arslanhan, Giorgio Scita, Etienne Formstecher, Maria Carla Parrini, Jinchao Yu, Institut Curie, Unité de génétique et biologie des cancers ( U830 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut Curie-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Compartimentation et dynamique cellulaires ( CDC ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -INSTITUT CURIE-Centre National de la Recherche Scientifique ( CNRS ), BioImaging Cell and Tissue Core Facility ( PICT-IBiSA ), INSTITUT CURIE, Mécanismes moléculaires du transport intracellulaire, Université Pierre et Marie Curie - Paris 6 ( UPMC ) -INSTITUT CURIE-Centre National de la Recherche Scientifique ( CNRS ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -INSTITUT CURIE-Centre National de la Recherche Scientifique ( CNRS ), Hybrigenics [Paris], Hybrigenics, Institut de Biologie Intégrative de la Cellule ( I2BC ), Université Paris-Sud - Paris 11 ( UP11 ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay-Centre National de la Recherche Scientifique ( CNRS ), Laboratoire de Biochimie de l'Ecole polytechnique ( BIOC ), Centre National de la Recherche Scientifique ( CNRS ) -École polytechnique ( X ), Fondazione Istituto FIRC di Oncologia Molecolare (IFOM), Institut Curie [Paris], Unité de génétique et biologie des cancers (U830), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Compartimentation et dynamique cellulaires (CDC), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut Curie [Paris]-Centre National de la Recherche Scientifique (CNRS), BioImaging Cell and Tissue Core Facility (PICT-IBiSA), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut Curie [Paris]-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut Curie [Paris]-Centre National de la Recherche Scientifique (CNRS), Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Assemblage moléculaire et intégrité du génome (AMIG), Département Biochimie, Biophysique et Biologie Structurale (B3S), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Biochimie de l'Ecole polytechnique (BIOC), École polytechnique (X)-Centre National de la Recherche Scientifique (CNRS), IFOM, Istituto FIRC di Oncologia Molecolare (IFOM), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5), Centre National de la Recherche Scientifique (CNRS)-Institut Curie [Paris]-Université Pierre et Marie Curie - Paris 6 (UPMC), Centre National de la Recherche Scientifique (CNRS)-Institut Curie [Paris]-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut Curie [Paris]-Université Pierre et Marie Curie - Paris 6 (UPMC), Centre National de la Recherche Scientifique ( CNRS ) -INSTITUT CURIE-Université Pierre et Marie Curie - Paris 6 ( UPMC ), Centre National de la Recherche Scientifique ( CNRS ) -INSTITUT CURIE-Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Centre National de la Recherche Scientifique ( CNRS ) -INSTITUT CURIE-Université Pierre et Marie Curie - Paris 6 ( UPMC ), École polytechnique ( X ) -Centre National de la Recherche Scientifique ( CNRS ), IFOM, Istituto FIRC di Oncologia Molecolare ( IFOM ), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS)-Institut Curie-Université Pierre et Marie Curie - Paris 6 (UPMC), Centre National de la Recherche Scientifique (CNRS)-Institut Curie-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut Curie-Université Pierre et Marie Curie - Paris 6 (UPMC), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Saclay, Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Saclay-Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Saclay-Institut de Biologie Intégrative de la Cellule (I2BC), and Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Saclay-Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Saclay

Subjects
0301 basic medicine, [SDV]Life Sciences [q-bio], Cell, Vesicular Transport Proteins, Motility, Exocyst, Biology, Exocytosis, 03 medical and health sciences, Cell Movement, medicine, Humans, Wave, Actin, Adaptor Proteins, Signal Transducing, [ SDV ] Life Sciences [q-bio], Effector, Rac1 gtpase, Cell migration, Cell Biology, Wiskott-Aldrich Syndrome Protein Family, Cell biology, Ral, Cytoskeletal Proteins, Protein Subunits, HEK293 Cells, 030104 developmental biology, medicine.anatomical_structure, Multiprotein Complexes, Cell Surface Extensions, Protein Binding
Abstract

International audience; Coordination between membrane trafficking and actin polymerization is fundamental in cell migration, but a dynamic view of the underlying molecular mechanisms is still missing. The Rac1 GTPase controls actin polymerization at protrusions by interacting with its effector, the Wave regulatory complex (WRC). The exocyst complex, which functions in polarized exocytosis, has been involved in the regulation of cell motility. Here, we show a physical and functional connection between exocyst and WRC. Purified components of exocyst and WRC directly associate in vitro, and interactions interfaces are identified. The exocyst-WRC interaction is confirmed in cells by co-immunoprecipitation and is shown to occur independently of the Arp2/3 complex. Disruption of the exocyst-WRC interaction leads to impaired migration. By using time-lapse microscopy coupled to image correlation analysis, we visualized the trafficking of the WRC towards the front of the cell in nascent protrusions. The exocyst is necessary for WRC recruitment at the leading edge and for resulting cell edge movements. This direct link between the exocyst and WRC provides a new mechanistic insight into the spatio-temporal regulation of cell migration.

Published
2016
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15. Prediction of homo- and hetero-protein complexes by protein docking and template-based modeling: a CASP-CAPRI experiment

Author

Eichiro Ichiishi, Dmitri Beglov, Bernard Maigret, Gyu Rie Lee, Artem B. Mamonov, Shoshana J. Wodak, Jonathan C. Fuller, Dima Kozakov, Jong Young Joung, Petr Popov, Xiaofeng Yu, Keehyoung Joo, João P. G. L. M. Rodrigues, Anna Vangone, Koen M. Visscher, Xiaoqin Zou, Paul A. Bates, Andriy Kryshtafovych, Shourya S. Roy Burman, Daisuke Kihara, Romina Oliva, Efrat Ben-Zeev, Jeffrey J. Gray, Yang Shen, Li C. Xue, Sameer Velankar, Emilie Neveu, Shruthi Viswanath, Dina Schneidman-Duhovny, Juan Esquivel-Rodríguez, Mieczyslaw Torchala, Amit Roy, Alexandre M. J. J. Bonvin, David R. Hall, Tanggis Bohnuud, Xusi Han, David W. Ritchie, Ron Elber, Daisuke Kuroda, Zhiwei Ma, Joan Segura, Carlos A. Del Carpio, Nicholas A. Marze, Jong Yun Kim, Andrej Sali, Petras J. Kundrotas, Ezgi Karaca, Neil J. Bruce, Chaok Seok, Panagiotis L. Kastritis, Shen You Huang, Ilya A. Vakser, Lim Heo, Sanbo Qin, Raphael A. G. Chaleil, Adrien S. J. Melquiond, Miguel Romero-Durana, Anisah W. Ghoorah, Surendra S. Negi, Andrey Tovchigrechko, Françoise Ochsenbein, Narcis Fernandez-Fuentes, Liming Qiu, Miriam Eisenstein, Mehdi Nellen, Marie-Dominique Devignes, Lenna X. Peterson, Jinchao Yu, Minkyung Baek, Brian G. Pierce, Hasup Lee, Toshiyuki Oda, Rebecca C. Wade, Raphael Guerois, Juan Fernández-Recio, Iain H. Moal, Edrisse Chermak, Sergei Grudinin, Sangwoo Park, Ivan Anishchenko, Chengfei Yan, Thom Vreven, Kentaro Tomii, Bing Xia, Hyung Rae Kim, Chiara Pallara, Jooyoung Lee, Kazunori D. Yamada, Xianjin Xu, Kenichiro Imai, Zhiping Weng, Luigi Cavallo, Tyler M. Borrman, Jianlin Cheng, Marc F. Lensink, Huan-Xiang Zhou, Jilong Li, Gydo C. P. van Zundert, Brian Jiménez-García, Tsukasa Nakamura, Scott E. Mottarella, Sandor Vajda, Institut de Recherche Interdisciplinaire [Villeneuve d'Ascq] ( IRI ), Université de Lille, Sciences et Technologies-Université de Lille, Droit et Santé-Centre National de la Recherche Scientifique ( CNRS ), European Molecular Biology Laboratory, European Bioinformatics Institute, Genome Center [UC Davis], University of California at Davis, Research Support Computing [Columbia], University of Missouri-Columbia, Bioinformatics Consortium and Department of Computer Science [Columbia], Department of Bioengineering and Therapeutic Sciences, University of California [San Francisco] ( UCSF ), Department of Pharmaceutical Chemistry, Department of Bioengineering and Therapeutic Sciences, Department of Pharmaceutical Chemistry, University of California [San Francisco] ( UCSF ) -California Institute for Quantitative Biosciences, GN7 of the National Institute for Bioinformatics (INB) and Biocomputing Unit, Centro Nacional de Biotecnología (CSIC), Institute of Biological, Environmental and Rural Sciences ( IBERS ), Institute for Computational Engineering and Sciences [Austin] ( ICES ), University of Texas at Austin [Austin], Department of Computer Science, Department of Chemistry, Algorithms for Modeling and Simulation of Nanosystems ( NANO-D ), Inria Grenoble - Rhône-Alpes, Institut National de Recherche en Informatique et en Automatique ( Inria ) -Institut National de Recherche en Informatique et en Automatique ( Inria ) -Laboratoire Jean Kuntzmann ( LJK ), Université Pierre Mendès France - Grenoble 2 ( UPMF ) -Université Joseph Fourier - Grenoble 1 ( UJF ) -Institut Polytechnique de Grenoble - Grenoble Institute of Technology-Centre National de la Recherche Scientifique ( CNRS ) -Université Grenoble Alpes ( UGA ) -Université Pierre Mendès France - Grenoble 2 ( UPMF ) -Université Joseph Fourier - Grenoble 1 ( UJF ) -Institut Polytechnique de Grenoble - Grenoble Institute of Technology-Centre National de la Recherche Scientifique ( CNRS ) -Université Grenoble Alpes ( UGA ) -Institut National Polytechnique de Grenoble ( INPG ), Moscow Institute of Physics and Technology [Moscow] ( MIPT ), Seoul National University [Seoul], Florida State University [Tallahassee] ( FSU ), Computational Algorithms for Protein Structures and Interactions ( CAPSID ), Inria Nancy - Grand Est, Institut National de Recherche en Informatique et en Automatique ( Inria ) -Institut National de Recherche en Informatique et en Automatique ( Inria ) -Department of Complex Systems, Artificial Intelligence & Robotics ( LORIA - AIS ), Laboratoire Lorrain de Recherche en Informatique et ses Applications ( LORIA ), Institut National de Recherche en Informatique et en Automatique ( Inria ) -Université de Lorraine ( UL ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut National de Recherche en Informatique et en Automatique ( Inria ) -Université de Lorraine ( UL ) -Centre National de la Recherche Scientifique ( CNRS ) -Laboratoire Lorrain de Recherche en Informatique et ses Applications ( LORIA ), Institut National de Recherche en Informatique et en Automatique ( Inria ) -Université de Lorraine ( UL ) -Centre National de la Recherche Scientifique ( CNRS ) -Université de Lorraine ( UL ) -Centre National de la Recherche Scientifique ( CNRS ), University of Mauritius, Biomolecular Modelling Laboratory, The Francis Crick Institute, Lincoln's Inn Fields Laboratory, G-INCPM, Weizmann Institute of Science, Chemical Research Support [Rehovot], Sealy Center for Structural Biology and Molecular Biophysics, The University of Texas Medical Branch ( UTMB ), Program in Bioinformatics and Integrative Biology [Worcester], University of Massachusetts Medical School [Worcester] ( UMASS ), Institut de Biologie Intégrative de la Cellule ( I2BC ), Université Paris-Saclay-Centre National de la Recherche Scientifique ( CNRS ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Sud - Paris 11 ( UP11 ), Bijvoet Center for Biomolecular Research [Utrecht], Utrecht University [Utrecht], Dalton Cardiovascular Research Center [Columbia], Department of Computer Science [Columbia], Informatics Intitute, Department of Biochemistry, University of Missouri, UNIVERSITY OF MISSOURI, Toyota Technological Institute at Chicago [Chicago] ( TTIC ), Department of Biological Sciences, Purdue University, Purdue University [West Lafayette], Department of Computer Science [Purdue], Bioinformatics and Computational Biosciences Branch, Rocky Mountain Laboratories, Molecular and Cellular Modeling Group, Heidelberg Institute of Theoretical Studies, Center for Molecular Biology ( ZMBH ), Universität Heidelberg [Heidelberg], Interdisciplinary Center for Scientific Computing ( IWR ), Department of Molecular Biosciences [Lawrence], University of Kansas [Lawrence] ( KU ), Computational Biology Research Center ( CBRC ), National Institute of Advanced Industrial Science and Technology ( AIST ), Graduate School of Frontier Sciences, The University of Tokyo, Joint BSC-CRG-IRB Research Program in Computational Biology, Barcelona Supercomputing Center - Centro Nacional de Supercomputacion ( BSC - CNS ), Center for In-Silico Protein Science, Korea Institute for Advanced Study ( KIAS ), Center for Advanced Computation, Department of Biomedical Engineering [Boston], Boston University [Boston] ( BU ), Institute of Biological Diversity, International Pacific Institute of Indiana, Drosophila Genetic Resource Center, Kyoto Institute of Technology, International University of Health and Welfare Hospital ( IUHW Hospital ), International University of Health and Welfare Hospital, Department of Chemical and Biomolecular Engineering [Baltimore], Johns Hopkins University ( JHU ), Program in Molecular Biophysics [Baltimore], King Abdullah University of Science and Technology ( KAUST ), University of Naples, J Craig Venter Institute, Structural Biology Research Center, VIB, 1050 Brussels, Belgium, Institut de Recherche Interdisciplinaire [Villeneuve d'Ascq] (IRI), Université de Lille, Sciences et Technologies-Université de Lille, Droit et Santé-Centre National de la Recherche Scientifique (CNRS), European Bioinformatics Institute [Hinxton] (EMBL-EBI), EMBL Heidelberg, University of California [Davis] (UC Davis), University of California (UC)-University of California (UC), University of Missouri [Columbia] (Mizzou), University of Missouri System, University of California [San Francisco] (UC San Francisco), Centro Nacional de Biotecnología [Madrid] (CNB-CSIC), Consejo Superior de Investigaciones Científicas [Madrid] (CSIC)-Consejo Superior de Investigaciones Científicas [Madrid] (CSIC), Institute of Biological, Environmental and Rural Sciences (IBERS), Institute for Computational Engineering and Sciences [Austin] (ICES), Algorithms for Modeling and Simulation of Nanosystems (NANO-D), Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Laboratoire Jean Kuntzmann (LJK ), Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Institut National de Recherche en Informatique et en Automatique (Inria)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Moscow Institute of Physics and Technology [Moscow] (MIPT), Seoul National University [Seoul] (SNU), Florida State University [Tallahassee] (FSU), Computational Algorithms for Protein Structures and Interactions (CAPSID), Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Department of Complex Systems, Artificial Intelligence & Robotics (LORIA - AIS), Laboratoire Lorrain de Recherche en Informatique et ses Applications (LORIA), Institut National de Recherche en Informatique et en Automatique (Inria)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche en Informatique et en Automatique (Inria)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS)-Laboratoire Lorrain de Recherche en Informatique et ses Applications (LORIA), Institut National de Recherche en Informatique et en Automatique (Inria)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), Biomolecular Modelling Laboratory [London], The Francis Crick Institute [London], Weizmann Institute of Science [Rehovot, Israël], The University of Texas Medical Branch (UTMB), University of Massachusetts Medical School [Worcester] (UMASS), University of Massachusetts System (UMASS)-University of Massachusetts System (UMASS), Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Assemblage moléculaire et intégrité du génome (AMIG), Département Biochimie, Biophysique et Biologie Structurale (B3S), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), University of Missouri System-University of Missouri System, Toyota Technological Institute at Chicago [Chicago] (TTIC), Department of Biological Sciences [Lafayette IN], Heidelberg Institute for Theoretical Studies (HITS ), Center for Molecular Biology (ZMBH), Universität Heidelberg [Heidelberg] = Heidelberg University, Interdisciplinary Center for Scientific Computing (IWR), University of Kansas [Lawrence] (KU), Computational Biology Research Center (CBRC), National Institute of Advanced Industrial Science and Technology (AIST), The University of Tokyo (UTokyo), Barcelona Supercomputing Center - Centro Nacional de Supercomputacion (BSC - CNS), Korea Institute for Advanced Study (KIAS), Boston University [Boston] (BU), International University of Health and Welfare Hospital (IUHW Hospital), Johns Hopkins University (JHU), King Abdullah University of Science and Technology (KAUST), University of Naples Federico II = Università degli studi di Napoli Federico II, J. Craig Venter Institute, VIB-VUB Center for Structural Biology [Bruxelles], VIB [Belgium], Centre National de la Recherche Scientifique (CNRS)-Université de Lille, Droit et Santé-Université de Lille, Sciences et Technologies, University of California-University of California, University of California [San Francisco] (UCSF), Centre National de la Recherche Scientifique (CNRS)-Université de Lorraine (UL)-Institut National de Recherche en Informatique et en Automatique (Inria)-Centre National de la Recherche Scientifique (CNRS)-Université de Lorraine (UL)-Institut National de Recherche en Informatique et en Automatique (Inria)-Laboratoire Lorrain de Recherche en Informatique et ses Applications (LORIA), Centre National de la Recherche Scientifique (CNRS)-Université de Lorraine (UL)-Institut National de Recherche en Informatique et en Automatique (Inria)-Centre National de la Recherche Scientifique (CNRS)-Université de Lorraine (UL), University of Naples Federico II, Barcelona Supercomputing Center, NMR Spectroscopy, and Sub NMR Spectroscopy

Subjects
0301 basic medicine, Protein Conformation, alpha-Helical, Protein Folding, Computer science, International Cooperation, Amino Acid Motifs, Oligomer state, Homoprotein, DATA-BANK, computer.software_genre, Molecular Docking Simulation, Biochemistry, CAPRI Round 30, DESIGN, Structural Biology, ALIGN, Blind prediction, AFFINITY, Protein interaction, Enginyeria biomèdica [Àrees temàtiques de la UPC], ZDOCK, Oligomer State, computer.file_format, Articles, Protein structure prediction, Proteïnes--Investigació, 3. Good health, WEB SERVER, CASP, Thermodynamics, Data mining, CAPRI, Protein docking, Molecular Biology, Algorithms, INTERFACES, Protein Binding, [ INFO.INFO-MO ] Computer Science [cs]/Modeling and Simulation, Bioinformatics, STRUCTURAL BIOLOGY, Computational biology, Molecular Dynamics Simulation, Article, 03 medical and health sciences, [ INFO.INFO-BI ] Computer Science [cs]/Bioinformatics [q-bio.QM], Heteroprotein, Humans, Protein binding, Macromolecular docking, Protein Interaction Domains and Motifs, Homology modeling, ALGORITHM, Protein-protein docking, Internet, Binding Sites, Models, Statistical, 030102 biochemistry & molecular biology, Bacteria, Sequence Homology, Amino Acid, Computational Biology, Proteins, Protein Data Bank, [INFO.INFO-MO]Computer Science [cs]/Modeling and Simulation, Protein Structure, Tertiary, 030104 developmental biology, Structural biology, Docking (molecular), Protein structure, Protein Conformation, beta-Strand, Protein Multimerization, oligomer state, blind prediction, protein interaction, protein docking, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], computer, Software
Abstract

We present the results for CAPRI Round 30, the first joint CASP-CAPRI experiment, which brought together experts from the protein structure prediction and protein–protein docking communities. The Round comprised 25 targets from amongst those submitted for the CASP11 prediction experiment of 2014. The targets included mostly homodimers, a few homotetramers, and two heterodimers, and comprised protein chains that could readily be modeled using templates from the Protein Data Bank. On average 24 CAPRI groups and 7 CASP groups submitted docking predictions for each target, and 12 CAPRI groups per target participated in the CAPRI scoring experiment. In total more than 9500 models were assessed against the 3D structures of the corresponding target complexes. Results show that the prediction of homodimer assemblies by homology modeling techniques and docking calculations is quite successful for targets featuring large enough subunit interfaces to represent stable associations. Targets with ambiguous or inaccurate oligomeric state assignments, often featuring crystal contact-sized interfaces, represented a confounding factor. For those, a much poorer prediction performance was achieved, while nonetheless often providing helpful clues on the correct oligomeric state of the protein. The prediction performance was very poor for genuine tetrameric targets, where the inaccuracy of the homology-built subunit models and the smaller pair-wise interfaces severely limited the ability to derive the correct assembly mode. Our analysis also shows that docking procedures tend to perform better than standard homology modeling techniques and that highly accurate models of the protein components are not always required to identify their association modes with acceptable accuracy. We are most grateful to the PDBe at the European Bioinformatics Institute in Hinxton, UK, for hosting the CAPRI website. Our deepest thanks go to all the structural biologists and to the following structural genomics initiatives: Northeast Structural Genomics Consortium, Joint Center for Structural Genomics, NatPro PSI:Biology, New York Structural Genomics Research Center, Midwest Center for Structural Genomics, Structural Genomics Consortium, for contributing the targets for this joint CASP-CAPRI experiment. MFL acknowledges support from the FRABio FR3688 Research Federation “Structural & Functional Biochemistry of Biomolecular Assemblies.”

Published
2016
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16. PPI4DOCK: Large scale assessment of the use of homology models in free docking over more than 1000 realistic targets

Author

Jinchao Yu, Raphael Guerois, Assemblage moléculaire et intégrité du génome ( AMIG ), Département Biochimie, Biophysique et Biologie Structurale ( B3S ), Institut de Biologie Intégrative de la Cellule ( I2BC ), Université Paris-Sud - Paris 11 ( UP11 ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay-Centre National de la Recherche Scientifique ( CNRS ) -Université Paris-Sud - Paris 11 ( UP11 ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay-Centre National de la Recherche Scientifique ( CNRS ) -Institut de Biologie Intégrative de la Cellule ( I2BC ), Université Paris-Sud - Paris 11 ( UP11 ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay-Centre National de la Recherche Scientifique ( CNRS ) -Université Paris-Sud - Paris 11 ( UP11 ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay-Centre National de la Recherche Scientifique ( CNRS ), Assemblage moléculaire et intégrité du génome (AMIG), Département Biochimie, Biophysique et Biologie Structurale (B3S), Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)

Subjects
0301 basic medicine, Statistics and Probability, [ SDV ] Life Sciences [q-bio], Computer science, [SDV]Life Sciences [q-bio], Computational Biology, Proteins, computer.software_genre, Biochemistry, Computer Science Applications, Molecular Docking Simulation, 03 medical and health sciences, Computational Mathematics, 030104 developmental biology, Computational Theory and Mathematics, Protein–ligand docking, Docking (molecular), Data mining, Molecular Biology, computer, Algorithms, Protein Binding
Abstract

Motivation: Protein–protein docking methods are of great importance for understanding interactomes at the structural level. It has become increasingly appealing to use not only experimental structures but also homology models of unbound subunits as input for docking simulations. So far we are missing a large scale assessment of the success of rigid-body free docking methods on homology models. Results: We explored how we could benefit from comparative modelling of unbound subunits to expand docking benchmark datasets. Starting from a collection of 3157 non-redundant, high X-ray resolution heterodimers, we developed the PPI4DOCK benchmark containing 1417 docking targets based on unbound homology models. Rigid-body docking by Zdock showed that for 1208 cases (85.2%), at least one correct decoy was generated, emphasizing the efficiency of rigid-body docking in generating correct assemblies. Overall, the PPI4DOCK benchmark contains a large set of realistic cases and provides new ground for assessing docking and scoring methodologies. Availability and Implementation: Benchmark sets can be downloaded from http://biodev.cea.fr/interevol/ppi4dock/ Contact: guerois@cea.fr Supplementary information: Supplementary data are available at Bioinformatics online.

Published
2016
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17. A novel hirudin derivative inhibiting thrombin without bleeding for subcutaneous injection

Author

Min Yu, Yanling Zhang, Jinchao Yu, Hou-Yan Song, Yixin Ma, Yaran Li, Qi Wang, Wei Mo, Bing Zhao, and Huang Yinong

Subjects
0301 basic medicine, Male, Time Factors, Epinephrine, Injections, Subcutaneous, Hirudin, Hemorrhage, 030204 cardiovascular system & hematology, Pharmacology, Ferric Compounds, Antithrombins, Rats, Sprague-Dawley, 03 medical and health sciences, 0302 clinical medicine, Thrombin, Chlorides, Risk Factors, Antithrombotic, Mesenteric Vascular Occlusion, medicine, Bivalirudin, Animals, Humans, Thrombus, Blood Coagulation, Venous Thrombosis, Dose-Response Relationship, Drug, business.industry, Hematology, Hirudins, medicine.disease, Thrombosis, Peptide Fragments, Recombinant Proteins, Dabigatran, Mice, Inbred C57BL, Venous thrombosis, Disease Models, Animal, 030104 developmental biology, Direct thrombin inhibitor, Anesthesia, Blood Coagulation Tests, Collagen, business, Pulmonary Embolism, medicine.drug
Abstract

SummaryCurrently, anticoagulants would be used to prevent thrombosis. Thrombin is an effector enzyme for haemostasis and thrombosis. We designed a direct thrombin inhibitor peptide (DTIP) using molecular simulation and homology modelling and demonstrated that the C-terminus of DTIP interacts with exosite I, and N-terminus with the activity site of thrombin, respectively. DTIP interfered with thrombin-mediated coagulation in human, rat and mouse plasma (n=10 per group) and blocked clotting in human whole blood in vitro. When administered subcutaneously, DTIP showed potent and dose-dependent extension of aPTT, PT, TT and CT in rats (n=10 per group). The antithrombotic dose of DTIP induced significantly less bleeding than bivalirudin determined by transecting distal tail assay in rats. Furthermore, DTIP reached peak blood concentration in 0.5–1 hour and did not cause increased bleeding after five days of dosing compared to dabigatran etexilate. The antithrombotic effect of DTIP was evaluated in mice using lethal pulmonary thromboembolism model and FeCl3-induced mesenteric arteriole thrombus model. DTIP (1.0 mg/kg, sc) prevented deep venous thrombosis and increased the survival rate associated with pulmonary thromboembolism from 30 % to 80 %. Intravital microscopy showed that DTIP (1.0 mg/kg, sc) decelerated mesenteric arteriole thrombosis caused by FeCl3 injury. These data establish that DTIP is a novel antithrombotic agent that could be used to prevent thrombosis without conferring an increased bleeding risk.Supplementary Material to this article is available at www.thrombosis-online.com.

Published
2016

18. InterEvDock: a docking server to predict the structure of protein-protein interactions using evolutionary information

Author

Jinchao Yu, Jessica Andreani, Pierre Tufféry, Marek Vavrusa, Julien Rey, Raphael Guerois, Institut de Biologie Intégrative de la Cellule ( I2BC ), Université Paris-Saclay-Centre National de la Recherche Scientifique ( CNRS ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Sud - Paris 11 ( UP11 ), Molécules Thérapeutique in silico, Recherche de molécules à visée thérapeutique par approches In Silico ( MTI ), Université Paris Diderot - Paris 7 ( UPD7 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Assemblage moléculaire et intégrité du génome (AMIG), Département Biochimie, Biophysique et Biologie Structurale (B3S), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Molécules Thérapeutiques in silico (MTI), and Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
0301 basic medicine, [SDV]Life Sciences [q-bio], Sequence alignment, Computational biology, Biology, Bioinformatics, Molecular Docking Simulation, Protein–protein interaction, Evolution, Molecular, 03 medical and health sciences, User-Computer Interface, Protein structure, Genetics, Web Server issue, Macromolecular docking, Protein Interaction Maps, Internet, [ SDV ] Life Sciences [q-bio], Proteins, Benchmarking, 030104 developmental biology, Protein–ligand docking, Docking (molecular), User interface, Sequence Alignment, Software
Abstract

International audience; The structural modeling of protein-protein interactions is key in understanding how cell machineries cross-talk with each other. Molecular docking simulations provide efficient means to explore how two unbound protein structures interact. InterEvDock is a server for protein docking based on a free rigid-body docking strategy. A systematic rigid-body docking search is performed using the FRODOCK program and the resulting models are re-scored with InterEvScore and SOAP-PP statistical potentials. The InterEvScore potential was specifically designed to integrate co-evolutionary information in the docking process. InterEvDock server is thus particularly well suited in case homologous sequences are available for both binding partners. The server returns 10 structures of the most likely consensus models together with 10 predicted residues most likely involved in the interface. In 91% of all complexes tested in the benchmark, at least one residue out of the 10 predicted is involved in the interface, providing useful guidelines for mutagenesis. InterEvDock is able to identify a correct model among the top10 models for 49% of the rigid-body cases with evolutionary information, making it a unique and efficient tool to explore structural interactomes under an evolutionary perspective. The InterEvDock web interface is available at http://bioserv.rpbs.univ-paris-diderot.fr/services/InterEvDock/.

Published
2016
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