15 results on '"Dennis M. Krüger"'
Search Results
2. Exercise as a model to identify microRNAs linked to human cognition: a role for microRNA-409 and microRNA-501
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Maria Goldberg, Md Rezaul Islam, Cemil Kerimoglu, Camille Lancelin, Verena Gisa, Susanne Burkhardt, Dennis M. Krüger, Till Marquardt, Berend Malchow, Andrea Schmitt, Peter Falkai, Farahnaz Sananbenesi, and Andre Fischer
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Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
Abstract MicroRNAs have been linked to synaptic plasticity and memory function and are emerging as potential biomarkers and therapeutic targets for cognitive diseases. Most of these data stem from the analysis of model systems or postmortem tissue from patients which mainly represents an advanced stage of pathology. Due to the in-accessibility of human brain tissue upon experimental manipulation, it is still challenging to identify microRNAs relevant to human cognition, which is however a key step for future translational studies. Here, we employ exercise as an experimental model for memory enhancement in healthy humans with the aim to identify microRNAs linked to memory function. By analyzing the circulating smallRNAome we find a cluster of 18 microRNAs that are highly correlated to cognition. MicroRNA-409-5p and microRNA-501-3p were the most significantly regulated candidates. Functional analysis revealed that the two microRNAs are important for neuronal integrity, synaptic plasticity, and morphology. In conclusion, we provide a novel approach to identify microRNAs linked to human memory function.
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- 2021
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3. Micelle Maker: An Online Tool for Generating Equilibrated Micelles as Direct Input for Molecular Dynamics Simulations
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Dennis M. Krüger and Shina C. L. Kamerlin
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Chemistry ,QD1-999 - Published
- 2017
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4. De novo active sites for resurrected Precambrian enzymes
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Valeria A. Risso, Sergio Martinez-Rodriguez, Adela M. Candel, Dennis M. Krüger, David Pantoja-Uceda, Mariano Ortega-Muñoz, Francisco Santoyo-Gonzalez, Eric A. Gaucher, Shina C. L. Kamerlin, Marta Bruix, Jose A. Gavira, and Jose M. Sanchez-Ruiz
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Science - Abstract
The emergence of novel catalytic functions in ancient proteins likely played a role in the evolution of modern enzymes. Here, the authors use protein sequences from Precambrian beta-lactamases and demonstrate that a single hydrophobic-to-ionizable amino acid mutation can lead to substantial Kemp eliminase activity.
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- 2017
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5. Interferon-driven brain phenotype in a mouse model of RNaseT2 deficient leukoencephalopathy
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Anne Winkler, Jonas Franz, Marco Henneke, Andre Fischer, Peter Rehling, A. Alia, Abhishek Aich, Hauke B. Werner, Simone Schröder, Samy Hakroush, Eva Bartok, Katharina Ternka, Charlotte Schob, Julia Kitz, Susann Boretius, Dennis M. Krüger, Robert Epple, M. Sadman Sakib, Silvia Zampar, Gunther Hartmann, Matthias Kettwig, Lalit Kaurani, Stefan Nessler, Kristin Wendland, Oliver Wirths, Jutta Gärtner, Marco Prinz, and Christine Stadelmann
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Male ,metabolism [CD8-Positive T-Lymphocytes] ,Neuroimmunology ,genetics [Leukoencephalopathies] ,General Physics and Astronomy ,CD8-Positive T-Lymphocytes ,metabolism [Memory T Cells] ,Leukoencephalopathy ,metabolism [Cognitive Dysfunction] ,Mice ,Leukoencephalopathies ,Mice, Knockout ,Multidisciplinary ,metabolism [Endoribonucleases] ,pathology [Leukoencephalopathies] ,Flow Cytometry ,Immunohistochemistry ,Magnetic Resonance Imaging ,medicine.anatomical_structure ,metabolism [Leukoencephalopathies] ,Female ,ddc:500 ,Neuroglia ,Genotype ,Science ,Encephalopathy ,Biology ,Real-Time Polymerase Chain Reaction ,General Biochemistry, Genetics and Molecular Biology ,Article ,White matter ,Memory T Cells ,Atrophy ,Downregulation and upregulation ,Endoribonucleases ,medicine ,Animals ,Humans ,Cognitive Dysfunction ,Neurodegeneration ,metabolism [Neuroglia] ,Neuroinflammation ,Cerebral atrophy ,Innate immune system ,genetics [Cognitive Dysfunction] ,General Chemistry ,medicine.disease ,Disease Models, Animal ,Immunology ,genetics [Endoribonucleases] - Abstract
Infantile-onset RNaseT2 deficient leukoencephalopathy is characterised by cystic brain lesions, multifocal white matter alterations, cerebral atrophy, and severe psychomotor impairment. The phenotype is similar to congenital cytomegalovirus brain infection and overlaps with type I interferonopathies, suggesting a role for innate immunity in its pathophysiology. To date, pathophysiological studies have been hindered by the lack of mouse models recapitulating the neuroinflammatory encephalopathy found in patients. In this study, we generated Rnaset2−/− mice using CRISPR/Cas9-mediated genome editing. Rnaset2−/− mice demonstrate upregulation of interferon-stimulated genes and concurrent IFNAR1-dependent neuroinflammation, with infiltration of CD8+ effector memory T cells and inflammatory monocytes into the grey and white matter. Single nuclei RNA sequencing reveals homeostatic dysfunctions in glial cells and neurons and provide important insights into the mechanisms of hippocampal-accentuated brain atrophy and cognitive impairment. The Rnaset2−/− mice may allow the study of CNS damage associated with RNaseT2 deficiency and may be used for the investigation of potential therapies., Studies on interferon-driven brain pathology have so far been hampered by the lack of appropriate animal models. Here the authors characterize RNASET2-deficient mice and show that neuroinflammation and brain atrophy are IFNAR1-dependent.
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- 2021
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6. Postnatal expression of the lysine methyltransferase SETD1B is essential for learning and the regulation of neuron‐enriched genes
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Julia Cha, M. Sadman Sakib, Elisabeth M. Zeisberg, Gregor Eichele, Jiayin Zhou, Ranjit Pradhan, A. Francis Stewart, Dennis M. Krüger, Rezaul Islam, Andrea Kranz, Tonatiuh Pena Centeno, Parth Devesh Joshi, Xingbo Xu, Sophie Schröder, Cemil Kerimoglu, Lalit Kaurani, Andre Fischer, and Alexandra Michurina
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metabolism [Myeloid-Lymphoid Leukemia Protein] ,Methyltransferase ,metabolism [Histones] ,genetics [Transcriptome] ,metabolism [Hippocampus] ,Cre recombinase ,Hippocampus ,Epigenesis, Genetic ,Histones ,0302 clinical medicine ,Gene expression ,Histone methylation ,Mice, Knockout ,Neurons ,0303 health sciences ,biology ,General Neuroscience ,Methylation ,Articles ,Cell biology ,ChIP-seq ,Histone ,KMT2A ,metabolism [Neurons] ,histone-methylation ,Kmt2a protein, mouse ,Histone methyltransferase ,metabolism [Histone-Lysine N-Methyltransferase] ,genetics [Histone-Lysine N-Methyltransferase] ,learning and memory ,Transcription Initiation Site ,Myeloid-Lymphoid Leukemia Protein ,Kmt2b protein, mouse ,General Biochemistry, Genetics and Molecular Biology ,deficiency [Histone-Lysine N-Methyltransferase] ,Article ,cognitive diseases ,03 medical and health sciences ,metabolism [Integrases] ,Memory ,ddc:570 ,Animals ,Learning ,physiology [Learning] ,metabolism [Cell Nucleus] ,Molecular Biology ,physiology [Memory] ,030304 developmental biology ,Cell Nucleus ,General Immunology and Microbiology ,Integrases ,metabolism [Calcium-Calmodulin-Dependent Protein Kinase Type 2] ,Histone-Lysine N-Methyltransferase ,Mice, Inbred C57BL ,ChIP‐seq ,Animals, Newborn ,Gene Expression Regulation ,Chromatin, Transcription & Genomics ,biology.protein ,H3K4me3 ,Calcium-Calmodulin-Dependent Protein Kinase Type 2 ,Transcriptome ,histone H3 trimethyl Lys4 ,histone‐methylation ,030217 neurology & neurosurgery ,Neuroscience - Abstract
In mammals, histone 3 lysine 4 methylation (H3K4me) is mediated by six different lysine methyltransferases. Among these enzymes, SETD1B (SET domain containing 1b) has been linked to syndromic intellectual disability in human subjects, but its role in the mammalian postnatal brain has not been studied yet. Here, we employ mice deficient for Setd1b in excitatory neurons of the postnatal forebrain, and combine neuron‐specific ChIP‐seq and RNA‐seq approaches to elucidate its role in neuronal gene expression. We observe that Setd1b controls the expression of a set of genes with a broad H3K4me3 peak at their promoters, enriched for neuron‐specific genes linked to learning and memory function. Comparative analyses in mice with conditional deletion of Kmt2a and Kmt2b histone methyltransferases show that SETD1B plays a more pronounced and potent role in regulating such genes. Moreover, postnatal loss of Setd1b leads to severe learning impairment, suggesting that SETD1B‐dependent regulation of H3K4me levels in postnatal neurons is critical for cognitive function., Comparative analyses of conditional deletion of mammalian H3K4 methyltransferases show a selective role for Setd1b in expression of neuron‐specific genes important for cognitive function.
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- 2021
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7. Protein-RNA interactions
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Saskia Neubacher, Tom N. Grossmann, Dennis M. Krüger, AIMMS, and Organic Chemistry
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0301 basic medicine ,Web server ,Magnetic Resonance Spectroscopy ,Bioinformatics ,chemistry [Alanine] ,Protein Conformation ,In silico ,RNA-binding protein ,Computational biology ,Biology ,computer.software_genre ,chemistry [RNA] ,metabolism [RNA-Binding Proteins] ,ribonucleoprotein ,03 medical and health sciences ,Structure-Activity Relationship ,chemistry [RNA-Binding Proteins] ,Protein Interaction Mapping ,ddc:610 ,Amino Acids ,protein–RNA complex ,Molecular Biology ,Protein secondary structure ,Ribonucleoprotein ,chemistry.chemical_classification ,chemistry [Amino Acids] ,Binding Sites ,Alanine ,030102 biochemistry & molecular biology ,RNA ,RNA-Binding Proteins ,secondary structure ,Alanine scanning ,Amino acid ,alanine scanning ,030104 developmental biology ,chemistry ,metabolism [RNA] ,Nucleic Acid Conformation ,computer ,Protein Binding - Abstract
Structural information about protein–RNA complexes supports the understanding of crucial recognition processes in the cell, and it can allow the development of high affinity ligands to interfere with these processes. In this respect, the identification of amino acid hotspots is particularly important. In contrast to protein–protein interactions, in silico approaches for protein–RNA interactions lag behind in their development. Herein, we report an analysis of available protein–RNA structures. We assembled a data set of 322 crystal and NMR structures and analyzed them regarding interface properties. In addition, we describe a computational alanine-scanning approach which provides interaction scores for interface amino acids, allowing the identification of potential hotspots in protein–RNA interfaces. We have made the computational approach available as an online tool, which allows interaction scores to be calculated for any structure of a protein–RNA complex by uploading atomic coordinates to the PRI HotScore web server (https://pri-hotscore.labs.vu.nl).
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- 2018
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8. Structure-Based Design of Non-Natural Macrocyclic Peptides that Inhibit Protein-Protein Interactions
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Dennis M. Krüger, Oliver Koch, Nicole Pospiech, Kerstin Wallraven, Sven Hennig, Adrian Glas, Laura Dietrich, Christian Ottmann, David Bier, Tom N. Grossmann, Organic Chemistry, AIMMS, and Chemical Biology
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0301 basic medicine ,Stereochemistry ,Chemie ,Medizin ,Crystallography, X-Ray ,Peptides, Cyclic ,Molecular Docking Simulation ,Article ,Protein–protein interaction ,Affinity maturation ,Structure-Activity Relationship ,03 medical and health sciences ,Peptide Library ,Drug Discovery ,Journal Article ,Animals ,Humans ,Structure–activity relationship ,Protein Interaction Domains and Motifs ,Amino Acids ,Binding site ,Peptide library ,Binding Sites ,Chemistry ,Combinatorial chemistry ,Chemical space ,030104 developmental biology ,Docking (molecular) ,Drug Design ,Molecular Medicine ,Protein Binding - Abstract
Macrocyclic peptides can interfere with challenging biomolecular targets including protein-protein interactions. Whereas there are various approaches that facilitate the identification of peptide-derived ligands, their evolution into higher affinity binders remains a major hurdle. We report a virtual screen based on molecular docking that allows the affinity maturation of macrocyclic peptides taking non-natural amino acids into consideration. These macrocycles bear large and flexible substituents that usually complicate the use of docking approaches. A virtual library containing more than 1400 structures was screened against the target focusing on docking poses with the core structure resembling a known bioactive conformation. Based on this screen, a macrocyclic peptide 22 involving two non-natural amino acids was evolved showing increased target affinity and biological activity. Predicted binding modes were verified by X-ray crystallography. The presented workflow allows the screening of large macrocyclic peptides with diverse modifications thereby expanding the accessible chemical space and reducing synthetic efforts. OA hybrid
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- 2017
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9. Translocation of an Intracellular Protein via Peptide-Directed Ligation
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Nicolas Brauckhoff, Hazem Salamon, Marcel Schmidt, Tom N. Grossmann, Petra Janning, Christiane Stiller, Dennis M. Krüger, Organic Chemistry, and AIMMS
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Peptide ,Chromosomal translocation ,Molecular Dynamics Simulation ,010402 general chemistry ,Protein labeling ,Ligands ,01 natural sciences ,Biochemistry ,Molecular dynamics ,Journal Article ,Humans ,Peptide ligand ,chemistry.chemical_classification ,010405 organic chemistry ,Chemistry ,Intracellular protein ,Proteins ,General Medicine ,0104 chemical sciences ,Cell biology ,Transport protein ,Protein Transport ,Molecular Medicine ,Ligation ,Peptides ,HeLa Cells - Abstract
Ligand-directed reactions allow chemical transformations at very low reactant concentrations and can thus provide access to efficient approaches for the post-translational modification of proteins. The development of these proximity-induced reactions is hampered by the number of appropriate ligands and the lack of design principles. Addressing these limitations, we report a proximity-induced labeling system which applies a moderate affinity peptide ligand. The design process was structure-guided and supported by molecular dynamics simulations. We show that selective protein labeling can be performed inside living cells enabling the subcellular translocation of a protein via ligand-directed chemistry for the first time.
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- 2017
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10. Increased Conformational Flexibility of a Macrocycle-Receptor Complex Contributes to Reduced Dissociation Rates
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Dennis M. Krüger, Christoph Rademacher, Eike-Christian Wamhoff, Adrian Glas, Tom N. Grossmann, Organic Chemistry, and AIMMS
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Receptor complex ,Magnetic Resonance Spectroscopy ,19f nmr spectroscopy ,Stereochemistry ,Peptidomimetic ,F-19 NMR spectroscopy ,Peptide ,Calorimetry ,Ligands ,010402 general chemistry ,01 natural sciences ,Catalysis ,Dissociation (chemistry) ,19F NMR spectroscopy ,Molecular dynamics ,binding kinetics ,chemistry.chemical_classification ,Binding Sites ,010405 organic chemistry ,Chemistry ,Communication ,Organic Chemistry ,cyclic peptides ,General Chemistry ,Kemi ,Communications ,Receptor–ligand kinetics ,Cyclic peptide ,Protein Structure, Tertiary ,0104 chemical sciences ,molecular dynamics simulation ,14-3-3 Proteins ,Cyclization ,peptidomimetics ,Chemical Sciences ,Thermodynamics ,Peptides ,F NMR spectroscopy ,Protein Binding - Abstract
Constraining a peptide in its bioactive conformation by macrocyclization represents a powerful strategy to design modulators of challenging biomolecular targets. This holds particularly true for the development of inhibitors of protein-protein interactions which often involve interfaces lacking defined binding pockets. Such flat surfaces are demanding targets for traditional small molecules rendering macrocyclic peptides promising scaffolds for novel therapeutics. However, the contribution of peptide dynamics to binding kinetics is barely understood which impedes the design process. Herein, we report unexpected trends in the binding kinetics of two closely related macrocyclic peptides that bind their receptor protein with high affinity. Isothermal titration calorimetry, 19F NMR experiments and molecular dynamics simulations reveal that increased conformational flexibility of the macrocycle–receptor complex reduces dissociation rates and contributes to complex stability. This observation has impact on macrocycle design strategies that have so far mainly focused on the stabilization of bioactive ligand conformations.
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- 2017
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11. De novo active sites for resurrected Precambrian enzymes
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Marta Bruix, Francisco Santoyo-Gonzalez, David Pantoja-Uceda, Mariano Ortega-Muñoz, Jose M. Sanchez-Ruiz, Shina Caroline Lynn Kamerlin, Sergio Martínez-Rodríguez, Valeria A. Risso, Dennis M. Krüger, Jose A. Gavira, Adela M. Candel, Eric A. Gaucher, Ministerio de Economía y Competitividad (España), and European Research Council
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0301 basic medicine ,Ancestral reconstruction ,Science ,General Physics and Astronomy ,Molecular Dynamics Simulation ,Protein Engineering ,Article ,beta-Lactamases ,General Biochemistry, Genetics and Molecular Biology ,Evolution, Molecular ,03 medical and health sciences ,Precambrian ,Catalytic Domain ,Escherichia coli ,Biologiska vetenskaper ,Amino acid replacement ,Biological sciences ,chemistry.chemical_classification ,Multidisciplinary ,biology ,Last universal ancestor ,Active site ,General Chemistry ,Protein engineering ,Biological Sciences ,030104 developmental biology ,Enzyme ,chemistry ,Biochemistry ,Evolutionary biology ,biology.protein - Abstract
Protein engineering studies often suggest the emergence of completely new enzyme functionalities to be highly improbable. However, enzymes likely catalysed many different reactions already in the last universal common ancestor. Mechanisms for the emergence of completely new active sites must therefore either plausibly exist or at least have existed at the primordial protein stage. Here, we use resurrected Precambrian proteins as scaffolds for protein engineering and demonstrate that a new active site can be generated through a single hydrophobic-to-ionizable amino acid replacement that generates a partially buried group with perturbed physico-chemical properties. We provide experimental and computational evidence that conformational flexibility can assist the emergence and subsequent evolution of new active sites by improving substrate and transition-state binding, through the sampling of many potentially productive conformations. Our results suggest a mechanism for the emergence of primordial enzymes and highlight the potential of ancestral reconstruction as a tool for protein engineering., This work was supported by Feder Funds, Grants from the Spanish Ministry of Economy and Competitiveness BIO2015-66426-R (J.M.S.-R.), CSD2009-00088 (J.M.S.-R.), CTQ2011-29299-C02-01 (F.S.-G.), CTQ2011-22514 (M.B.), BIO2016-74875-P (J.A.G.), ‘Factoría Española de Cristalización˜’, Consolider-Ingenio 2010 (J.A.G.) and CEI BioTic V19-2015 (V.A.R.), a Wallenberg Academy Fellowship (S.C.L.K.) and DuPont Young Professor Award (E.A.G.) and Grants NNX13AI08G and NNX13AI10G (E.A.G.) from NASA Exobiology. The European Research Council has provided financial support under the European Community’s Seventh Framework Programme (FP7/2007–2013)/ERC Grant Agreement No. 306474.
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- 2017
12. Towards targeting protein-protein interfaces with small molecules
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Christopher Pfleger, Dennis M. Krüger, Holger Gohlke, Alexander Metz, and Sina Kazemi
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lcsh:T58.5-58.64 ,Computer science ,lcsh:Information technology ,Rational design ,Nanotechnology ,Computational biology ,Plasma protein binding ,Library and Information Sciences ,Computer Graphics and Computer-Aided Design ,Fusion protein ,Small molecule ,Computer Science Applications ,Enzyme binding ,lcsh:Chemistry ,Protein structure ,lcsh:QD1-999 ,Docking (molecular) ,Oral Presentation ,Physical and Theoretical Chemistry ,Binding site - Abstract
A promising way to interfere with biological processes is through the control of protein-protein interactions by means of small molecules that modulate the formation of protein-protein complexes. Although the feasibility of this approach has been demonstrated in principle by recent results, many of the small-molecule modulators known to date have not been found by rational design approaches. In large part this is due to the challenges that one faces in dealing with protein binding epitopes compared to, e.g., enzyme binding pockets. Recent advances in the understanding of the energetics and dynamics of protein binding interfaces[1] and methodological developments in the field of structure-based drug design methods may open up a way to apply rational design approaches also for finding protein-protein interaction modulators.2 Here, we first show in a retrospective analysis of the well-investigated interleukin-2 system how I) potential binding sites in an interface can be identified from an unbound protein structure, II) the interface can be dissected in terms of energetic contributions of single residues, and III) one can make use of this knowledge for guiding the development of small-molecule modulators. When applied to a leukaemia-associated fusion protein in a prospective manner, the predictive character of the methodology is demonstrated [2]. Another challenge arises from the fact that protein-protein interfaces are flexible. In the second part, we thus demonstrate a novel approach for including protein flexibility into protein-ligand docking[3]. This approach is based on elastic potential grids, which provide an accurate and efficient representation of intermolecular interactions in fully-flexible docking.
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- 2011
13. Predicting protein-protein interactions with DrugScorePPI: fully-flexible docking, scoring, and in silico alanine-scanning
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P. C. Montes, José Ignacio Garzón, Dennis M. Krüger, and Holger Gohlke
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FoldX ,lcsh:T58.5-58.64 ,lcsh:Information technology ,Computer science ,education ,Fast Fourier transform ,Library and Information Sciences ,Alanine scanning ,Grid ,computer.software_genre ,Computer Graphics and Computer-Aided Design ,Computer Science Applications ,lcsh:Chemistry ,Protein structure ,lcsh:QD1-999 ,Docking (molecular) ,Searching the conformational space for docking ,Test set ,Poster Presentation ,Data mining ,Physical and Theoretical Chemistry ,Biological system ,computer - Abstract
Protein-protein complexes play key roles in all cellular signal transduction processes. Here, we present a fast and accurate computational approach to predict protein-protein interactions. The approach is based on DrugScorePPI, a knowledge-based scoring function for which pair potentials were derived from 851 complex structures and adapted against 309 experimental alanine scanning results. We developed the DrugScorePPI webserver [1], accessible at http://cpclab.uni-duesseldorf.de/dsppi, that is intended for identifying hotspot residues in protein-protein interfaces. For this, it allows performing computational alanine scanning of a protein-protein interface within a few minutes. Our approach has been successfully validated by application to an external test set of 22 alanine mutations in the interface of Ras/RalGDS and outperformed the widely used CC/PBSA, FoldX, and Robetta methods [1]. Next, DrugScorePPI was teamed with FRODOCK [2], a fast FFT-based protein-protein docking tool, in order to predict 3D structures of protein-protein complexes. When applied to datasets of 54 bound-bound (I) and 54 unbound-unbound (II) test cases, convincing results were obtained (docking success rate for complexes with rmsd < 10 A: I: ~80%; II: ~50%). Thus, we set out to evaluate whether our approach of deformable potential grids [3], previously developed for protein-ligand docking, also provides an accurate and efficient means for representing intermolecular interactions in fully-flexible protein-protein docking. The underlying idea is to adapt a 3D grid of potential field values, pre-calculated from an initial protein conformation by DrugScorePPI, to another conformation by moving grid intersection points in space, but keeping the potential field values constant. Protein movements are thereby translated into grid intersection displacements by coupling protein atoms to nearby grid intersection points by means of harmonic springs and modelling the irregular, deformable 3D grid as a homogeneous linear elastic body applying elasticity theory. Thus, new protein conformations can be sampled during a docking run without the need to re-calculate potential field values.
- Published
- 2011
14. DrugScorePPI for scoring protein-protein interactions: improving a knowledge-based scoring function by atomtype-based QSAR
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Dennis M. Krüger and Holger Gohlke
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Quantitative structure–activity relationship ,Binding free energy ,Correlation coefficient ,lcsh:T58.5-58.64 ,Computer science ,lcsh:Information technology ,Library and Information Sciences ,computer.software_genre ,Computer Graphics and Computer-Aided Design ,Protein–protein interaction ,Computer Science Applications ,Correlation ,lcsh:Chemistry ,Formalism (philosophy of mathematics) ,lcsh:QD1-999 ,Docking (molecular) ,Poster Presentation ,Data mining ,Physical and Theoretical Chemistry ,Biological system ,computer ,Root-mean-square deviation - Abstract
Protein-protein complexes are known to play key roles in many cellular processes. Therefore, knowledge of the three-dimensional structure of protein-complexes is of fundamental importance. A key goal in protein-protein docking is to identify near-native protein-complex structures. In this work, we address this problem by deriving a knowledge-based scoring function from protein-protein complex structures and further fine-tuning of the statistical potentials against experimentally determined alanine-scanning results. Based on the formalism of the DrugScore approach1, distance-dependent pair potentials are derived from 850 crystallographically determined protein-protein complexes 2. These DrugScorePPI potentials display quantitative differences compared to those of DrugScore, which was derived from protein-ligand complexes. When used as an objective function to score a non-redundant dataset of 54 targets with "unbound perturbation" solutions, DrugscorePPI was able to rank a near-native solution in the top ten in 89% and in the top five in 65% of the cases. Applied to a dataset of "unbound docking" solutions, DrugscorePPI was able to rank a near-native solution in the top ten in 100% and in the top five in 67% of the cases. Furthermore, Drugscore-PPI was used for computational alanine-scanning of a dataset of 18 targets with a total of 309 mutations to predict changes in the binding free energy upon mutations in the interface. Computed and experimental values showed a correlation of R2 = 0.34. To improve the predictive power, a QSAR-model was built based on 24 residue-specific atom types that improves the correlation coefficient to a value of 0.53, with a root mean square deviation of 0.89 kcal/mol. A Leave-One-Out analysis yields a correlation coefficient of 0.41. This clearly demonstrates the robustness of the model. The application to an independent validation dataset of alanine-mutations was used to show the predictive power of the method and yields a correlation coefficient of 0.51. Based on these findings, Drugscore-PPI was used to successful identify hotspots in multiple protein-interfaces. These results suggest that DrugscorePPI is an adequate method to score protein-protein interactions.
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15. DrugScorePPI knowledge-based potentials used as scoring and objective function in protein-protein docking.
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Dennis M Krüger, José Ignacio Garzón, Pablo Chacón, and Holger Gohlke
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Medicine ,Science - Abstract
The distance-dependent knowledge-based DrugScore(PPI) potentials, previously developed for in silico alanine scanning and hot spot prediction on given structures of protein-protein complexes, are evaluated as a scoring and objective function for the structure prediction of protein-protein complexes. When applied for ranking "unbound perturbation" ("unbound docking") decoys generated by Baker and coworkers a 4-fold (1.5-fold) enrichment of acceptable docking solutions in the top ranks compared to a random selection is found. When applied as an objective function in FRODOCK for bound protein-protein docking on 97 complexes of the ZDOCK benchmark 3.0, DrugScore(PPI)/FRODOCK finds up to 10% (15%) more high accuracy solutions in the top 1 (top 10) predictions than the original FRODOCK implementation. When used as an objective function for global unbound protein-protein docking, fair docking success rates are obtained, which improve by ∼ 2-fold to 18% (58%) for an at least acceptable solution in the top 10 (top 100) predictions when performing knowledge-driven unbound docking. This suggests that DrugScore(PPI) balances well several different types of interactions important for protein-protein recognition. The results are discussed in view of the influence of crystal packing and the type of protein-protein complex docked. Finally, a simple criterion is provided with which to estimate a priori if unbound docking with DrugScore(PPI)/FRODOCK will be successful.
- Published
- 2014
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