152 results on '"Yi Qin Gao"'
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2. Sequence‐dependent clustering properties of nucleotides fragments in an ionic solution
- Author
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Manas Mondal and Yi Qin Gao
- Subjects
General Chemistry - Published
- 2023
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3. Characterization of network hierarchy reflects cell state specificity in genome organization
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Jingyao Wang, Yue Xue, Yueying He, Hui Quan, Jun Zhang, and Yi Qin Gao
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Genetics ,Genetics (clinical) - Abstract
Dynamic chromatin structure acts as the regulator of transcription program in crucial processes including cancer and cell development, but a unified framework for characterizing chromatin structural evolution remains to be established. Here, we performed graph inferences on Hi-C data sets and derived the chromatin contact networks. We discovered significant decreases in information transmission efficiencies in chromatin of colorectal cancer (CRC) and T-cell acute lymphoblastic leukemia (T-ALL) compared to corresponding normal controls through graph statistics. Using network embedding in the Poincaré disk, the hierarchy depths of chromatin from CRC and T-ALL patients were found to be significantly shallower compared to their normal controls. A reverse trend of change in chromatin structure was observed during early embryo development. We found tissue-specific conservation of hierarchy order in chromatin contact networks. Our findings reveal the top-down hierarchy of chromatin organization, which is significantly attenuated in cancer.
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- 2023
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4. Reaction coordinates by nonlinear dimensionality reduction
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Zhen Zhang, Yao Kun Lei, Jun Zhang, and Yi Qin Gao
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Physical and Theoretical Chemistry - Abstract
Deriving reaction coordinates for the characterization of chemical reactions has long been a demanding task. In our previous work [ACS Cent. Sci. 3, 407 (2017)], the reaction coordinate of a (retro-) Claisen rearrangement in aqueous solution optimized through a Bayesian measure, a linear combination of bond lengths formation and breakage, was judged to be optimal among all trails. Here, considering the nonlinearity of the transition state, we use isometric mapping and locally linear embedding to obtain one reaction coordinate which is composed of a few collective variables. With these methods, we find a more reasonable and powerful one-dimensional reaction coordinate, which can well describe the reaction progression. To explore the reaction mechanism, we analyze the contribution of intrinsic molecular properties and the solvent-solute interactions to the nonlinear reaction coordinate. Furthermore, another coordinate is identified to characterize the heterogeneity of reaction mechanisms.
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- 2022
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5. Sequence-Specific Structural Features and Solvation Properties of Transcription Factor Binding DNA Motifs: Insights from Molecular Dynamics Simulation
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Piya Patra and Yi Qin Gao
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Binding Sites ,Materials Chemistry ,Humans ,DNA ,Nucleotide Motifs ,Molecular Dynamics Simulation ,Physical and Theoretical Chemistry ,Transcription Factors ,Protein Binding ,Surfaces, Coatings and Films - Abstract
Sequence-specific recognition of transcription factor (TF) binding motifs in the target site of DNA over the vast amount of non-target DNA is of primary importance for the transcriptional regulation of gene expression by the TFs. Binding of TFs to the target site of DNA relies not only on the direct contact formation but also on the structural and conformational features of DNA. Recognition of DNA structural features or shape readout by proteins is an important factor in the context of TF-DNA interaction. Based on the atomistic molecular simulation, here we report the sequence-dependent unique structural features, solvation, and ion-binding properties of biologically relevant AT- and GC-rich human TF binding motifs in DNA. Counterion and water distribution around the motif is found to be sensitive to the motif sequence, which is accompanied with the DNA shape features. The motif sequence affects the electrostatic potential along the grooves, and cytosine methylation alters the DNA shape features. Characteristic solvation properties of TF binding motif DNA fragments infer that an ionic environment and hydration influences are essential to describe TF-DNA interactions.
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- 2022
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6. DNA Sequence-Dependent Binding of Linker Histone gH1 Regulates Nucleosome Conformations
- Author
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Hong Zhang, Qin Yuan Huo, and Yi Qin Gao
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Histones ,Base Sequence ,Materials Chemistry ,DNA ,Physical and Theoretical Chemistry ,Chromatin ,Nucleosomes ,Protein Binding ,Surfaces, Coatings and Films - Abstract
Sequence-dependent binding between DNA and proteins in chromatin is an essential part of gene expression. Linker histone H1 is an important protein in the regulation of chromatin compartmentalization and compaction, and its binding with the nucleosome is sensitive to the DNA sequence. Although the interactions of H1 and DNA have been widely investigated, the mechanism of nucleosome conformation changes induced by the DNA-sequence-dependent binding with gH1 (globular H1.0) remains largely unclear at the atomic level. In the present molecular dynamics simulations, both linker and dyad DNAs were mutated to investigate the conformational changes of the nucleosome induced by the sequence-dependent binding of gH1 based on the on-dyad binding mode. Our results indicate that gH1 is insensitive to the DNA sequence of the dyad DNA but presents an apparent preference to linker DNA with an AT-rich sequence. Moreover, this specific binding induces the entry/exit region of a nucleosome to a tight conformation and regulates the accessibility of core histones. Considering that the entry/exit region of the nucleosome is a crucial binding site for many functional proteins related to gene expression, the conformational change at this region could represent an important gene regulation signal.
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- 2022
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7. Assisting and Accelerating NMR Assignment with Restrained Structure Prediction
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Sirui Liu, Haotian Chu, Yuhao Xie, Fangming Wu, Ningxi Ni, Chenghao Wang, Fangjing Mu, Jiachen Wei, Jun Zhang, Mengyun Chen, Junbin Li, Fan Yu, Hui Fu, Shenlin Wang, Changlin Tian, Zidong Wang, and Yi Qin Gao
- Abstract
NMR experiments can detect in situ structures and dynamic interactions, but the NMR assignment process requires expertise and is time-consuming, thereby limiting its applicability. Deep learning algorithms have been employed to aid in experimental data analysis. In this work, we developed a RASP model which can enhance structure prediction with restraints. Based on the Evoformer and structure module architecture of AlphaFold, this model can predict structure based on sequence and a flexible number of input restraints. Moreover, it can evaluate the consistency between the predicted structure and the imposed restraints. Based on this model, we constructed an iterative NMR NOESY peak assignment pipeline named FAAST, to accelerate assignment process of NOESY restraints and obtaining high quality structure ensemble. The RASP model and FAAST pipeline not only allow for the leveraging of experimental restraints to improve model prediction, but can also facilitate and expedite experimental data analysis with their integrated capabilities.
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- 2023
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8. High Li + coordinated solvation sheaths enable <scp>high‐quality</scp> Li metal anode
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Shizhi Huang, Yu‐Peng Huang, Yijie Xia, Jingyi Ding, Chengyuan Peng, Lulu Wang, Junrong Luo, Xin‐Xiang Zhang, Junrong Zheng, Yi Qin Gao, and Jitao Chen
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Materials Science (miscellaneous) ,Materials Chemistry ,Surfaces, Coatings and Films ,Electronic, Optical and Magnetic Materials - Published
- 2023
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9. <scp>SPONGE</scp> : A <scp>GPU‐Accelerated</scp> Molecular Dynamics Package with Enhanced Sampling and <scp>AI‐Driven</scp> Algorithms
- Author
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Yi Isaac Yang, Yijie Xia, Jiachen Wei, Lijiang Yang, Yi Qin Gao, and Yu-Peng Huang
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Molecular dynamics ,Chemistry ,Sampling (statistics) ,General Chemistry ,Computational science - Published
- 2021
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10. Effect of stereoregularity on excitation‐dependent fluorescence and room‐temperature phosphorescence of poly(2‐vinylpyridine)
- Author
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Hongxu Du, Wenjing Zhao, Yijie Xia, Siyu Xie, Yi Tao, Yi Qin Gao, Jie Zhang, and Xinhua Wan
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General Medicine - Published
- 2022
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11. Topological Constraints with Optimal Length Promote the Formation of Chromosomal Territories at Weakened Degree of Phase Separation
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Fan Song, Jiachen Wei, Hao Tian, Rui Zhou, Yingfeng Shao, and Yi Qin Gao
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Cell Nucleus ,Physics ,Loop (graph theory) ,Flexibility (anatomy) ,Degree (graph theory) ,Dissipative particle dynamics ,Topology ,Chromatin ,Chromosomes ,Critical length ,Surfaces, Coatings and Films ,medicine.anatomical_structure ,Materials Chemistry ,medicine ,Humans ,CpG Islands ,Interphase ,Physical and Theoretical Chemistry - Abstract
It is generally agreed that the nuclei of eukaryotic cells at interphase are partitioned into disjointed territories, with distinct regions occupied by certain chromosomes. However, the underlying mechanism for such territorialization is still under debate. Here we model chromosomes as coarse-grained block copolymers and to investigate the effect of loop domains (LDs) on the formation of compartments and territories based on dissipative particle dynamics. A critical length of LDs, which depends sensitively on the length of polymeric blocks, is obtained to minimize the degree of phase separation. This also applies to the two-polymer system: The critical length not only maximizes the degree of territorialization but also minimizes the degree of phase separation. Interestingly, by comparing with experimental data, we find the critical length for LDs and the corresponding length of blocks to be respectively very close to the mean length of topologically associating domains (TADs) and chromosomal segments with different densities of CpG islands for human chromosomes. The results indicate that topological constraints with optimal length can contribute to the formation of territories by weakening the degree of phase separation, which likely promotes the chromosomal flexibility in response to genetic regulations.
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- 2021
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12. Locating Transition Zone in Phase Space
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Yao-Kun Lei, Zhen Zhang, Xu Han, Yi Isaac Yang, Jun Zhang, and Yi Qin Gao
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Physical and Theoretical Chemistry ,Computer Science Applications - Abstract
Understanding the reaction mechanism is required for better control of chemical reactions and is usually achieved by locating transition states (TSs) along a proper one-dimensional coordinate called reaction coordinate (RC). The identification of RC can be very difficult for high-dimensional realistic systems. A number of methods have been proposed to tackle this problem. A machine learning method is developed here to incorporate the influence of velocity on the reaction process. The method is also free of the unbalanced label problem resulting from the rather low fraction of configurations near the TS and can be easily extended to large systems. It locates the transition zone in the phase space and defines the dividing surface with a high transmission coefficient. Moreover, considering that the reaction environment can not only change the reaction path but also activate the reactive mode through energy transfer, we devise two measures to quantify the influence of these two factors on the reaction process and find that solvents can assist the reaction by directly doing work along the reactive mode. Not surprisingly, there is a positive correlation between the efficiency of energy transfer into the reactive mode and the reaction rate.
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- 2022
13. Phase Transition between Crystalline Variants of Ordinary Ice
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Maodong Li, Jun Zhang, Haiyang Niu, Yao-Kun Lei, Xu Han, Lijiang Yang, Zhiqiang Ye, Yi Isaac Yang, and Yi Qin Gao
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General Materials Science ,Physical and Theoretical Chemistry - Abstract
Water is one of the most abundant molecules on Earth. However, this common and "simple" material has more than 18 different phases, which poses a great challenge to theoretically study the nature of water and ice. We designed two reaction coordinates that can distinguish between water and various ice states and used them to efficiently sample all possible states of the system in all-atom molecular dynamics simulation at ambient temperature and pressure. Various structural and thermodynamics properties, including the water-ice phase diagrams, can thus be calculated. We also present a simple model that successfully explains the thermodynamic stability of different ice states. Our work provides effective methods and data for theoretical studies of different phases of water and ice.
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- 2022
14. Microscopic model on indoor propagation of respiratory droplets
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Manas Mondal, Srabani Chakrabarty, Yi Qin Gao, Dhananjay Bhattacharyya, and Jaydeb Chakrabarti
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Computational Mathematics ,Structural Biology ,Organic Chemistry ,Biochemistry - Abstract
Indoor propagation of airborne diseases is yet poorly understood. Here, we theoretically study a microscopic model based on the motions of virus particles in a respiratory microdroplet, responsible for airborne transmission of diseases, to understand their indoor propagation. The virus particles are driven by a driving force that mimics force due to gushing of air by devices like indoor air conditioning along with the gravity. A viral particle within the droplet experiences viscous drag due to the droplet medium, force due to interfacial tension at the droplet boundary, the thermal forces and mutual interaction forces with the other viral particles. We use Brownian Dynamics (BD) simulations and scaling arguments to study the motion of the droplet, given by that of the center of mass of the viral assembly. The BD simulations show that in presence of the gravity force alone, the time the droplet takes to reach the ground level, defined by the gravitational potential energy being zero, from a vertical height H,t
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- 2022
15. Characterization of network hierarchy reflects cell-state specificity in genome organization
- Author
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Jingyao Wang, Yue Xue, Yueying He, Hui Quan, Jun Zhang, and Yi Qin Gao
- Abstract
Dynamic chromatin structure acts as the regulator of transcription program in crucial processes including cancer and cell development, but a unified framework for characterizing chromatin structural evolution remains to be established. Here, we performed graph inferences on Hi-C datasets and derived the chromatin contact networks (CCNs). We discovered significant decreases in information transmission efficiencies in CCNs of colorectal cancer (CRC) and T-lineage acute lymphoblastic leukemia (T-ALL) compared to corresponding normal controls through graph statistics. Through network embedding in Poincaré disk, the hierarchy depths of CCNs from CRC and T-ALL patients were found to be significantly shallower compared to their normal controls. A reverse trend of CCN change was observed for the transition from embryo to differentiated primary tissues. During early embryo developments of both human and mouse, the hierarchy of embedded chromatin structure gradually establishes. Additionally, we found tissue-specific conservation of hierarchy order in normal CCNs, which was disturbed in tumor. Our findings uncover the cell-state related hierarchical characteristics in chromatin structure, which reveal chromatin loci that play important roles in stabilizing the cellular conditions.
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- 2022
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16. Multi-scale gene regulation mechanism: Spatiotemporal transmission of genetic information
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Yue Xue, Jingyao Wang, Yueying He, Piya Patra, and Yi Qin Gao
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Histones ,Gene Expression Regulation ,Structural Biology ,Molecular Biology ,Chromatin ,Epigenesis, Genetic ,Transcription Factors - Abstract
Gene expression is regulated by many factors, including transcription factors, chromatin three-dimensional topology, modifications of DNA and histone proteins, and non-coding RNAs. The execution of these complex mechanisms requires an effectively coordinated regulation system. In this review, we emphasize that the multi-scale heterogeneous DNA sequence plays a fundamental and important role for gene expression activity and usage of different means of epigenetic regulation. We illustrate here that the chromatin structure organization provides a stage for spatiotemporal regulation between different genes or gene modules and to realize their downstream functional cooperation. Such a perspective expands our understanding of the central dogma: In addition to one-dimensional sequence information, inter-gene interactions can also be transferred from DNA and RNA to protein levels.
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- 2022
17. Computational Enhanced Hi-C data reveals the function of structural geometry in genomic regulation
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Yueying He, Yue Xue, Jingyao Wang, Yupeng Huang, Lu Liu, Yanyi Huang, and Yi Qin Gao
- Abstract
High-throughput chromosome conformation capture (Hi-C) technique profiles the genomic structure in a genome-wide fashion. The reproducibility and consistency of Hi-C data are essential in characterizing dynamics of genomic structures. We developed a diffusion-based method, CTG (Hi-C To Geometry), to deal with the technical bias induced by insufficient sampling in sequencing and obtain reliable gemeotric information of the chromatin. CTG properly quantifies dubiously weak or even undetected interactions and produces a consistent and reproducible framework for the 3D genomic structure. CTG allows for a reliable genome-wide insight on the alteration of genomic structures under different cellular conditions and reveals correlations between genomic-proximal genes at both transcriptional and translational levels. Cell-specific correspondence between gene-gene and corresponding protein-protein physical interactions, as well as that with the transcription correlation reveals the coordinated inter-molecular structural and regulatory information passage in the central dogma.
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- 2022
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18. Deep reinforcement learning of transition states
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Zhen Zhang, Yi Isaac Yang, Maodong Li, Jun Zhang, Lijiang Yang, Yi Qin Gao, Xu Han, and Yao-Kun Lei
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Chemical Physics (physics.chem-ph) ,FOS: Computer and information sciences ,Computer Science - Machine Learning ,Computer science ,FOS: Physical sciences ,General Physics and Astronomy ,Value (computer science) ,State (functional analysis) ,Function (mathematics) ,Transition state ,Machine Learning (cs.LG) ,Reaction dynamics ,Physics - Chemical Physics ,Bellman equation ,Path (graph theory) ,Reinforcement learning ,Physical and Theoretical Chemistry ,Algorithm - Abstract
Combining reinforcement learning (RL) and molecular dynamics (MD) simulations, we propose a machine-learning approach (RL$^\ddag$) to automatically unravel chemical reaction mechanisms. In RL$^\ddag$, locating the transition state of a chemical reaction is formulated as a game, where a virtual player is trained to shoot simulation trajectories connecting the reactant and product. The player utilizes two functions, one for value estimation and the other for policy making, to iteratively improve the chance of winning this game. We can directly interpret the reaction mechanism according to the value function. Meanwhile, the policy function enables efficient sampling of the transition paths, which can be further used to analyze the reaction dynamics and kinetics. Through multiple experiments, we show that RL{\ddag} can be trained tabula rasa hence allows us to reveal chemical reaction mechanisms with minimal subjective biases., Comment: version 1
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- 2021
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19. Enhanced Sampling Simulation Reveals How Solvent Influences Chirogenesis of the Intra-Molecular Diels-Alder Reaction
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Xu Han, Jun Zhang, Yi Isaac Yang, Zhen Zhang, Lijiang Yang, and Yi Qin Gao
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Cycloaddition Reaction ,Solvents ,Water ,Hydrogen Bonding ,Physical and Theoretical Chemistry ,Molecular Dynamics Simulation ,Computer Science Applications - Abstract
The timescale involved in chemical reactions is quite often beyond that of normal molecular dynamics simulations. Here, we combine metadynamics with selective integrated tempering sampling to simulate an intra-molecular Diels-Alder reaction in explicit solvents. Based on a one-dimensional collective variable obtained from harmonic linear discriminant analysis, four chiral isomers of products were observed in the simulation. Analyses of reactive trajectories showed that this reaction follows a concerted mechanism in all four solvents. In addition, the hydrogen bond between the reactant and water solvent plays an important role in the water-accelerated reaction mechanism. The dynamics of chirality formation varies significantly with solvents. The chirality of products forms significantly before the transition state, especially in ionic liquid.
- Published
- 2022
20. Microscopic Insight into pH-Dependent Conformational Dynamics and Noncanonical Base Pairing in Telomeric i-Motif DNA
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Manas Mondal and Yi Qin Gao
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General Materials Science ,Physical and Theoretical Chemistry - Abstract
Gene regulatory functions of noncanonical i-motif DNA are associated with dynamic i-motif formation in the cellular environment and pH variation. With atomistic simulations, we show the dramatic influence of solvent pH on the conformational dynamics of biologically relevant telomeric i-motif DNA coupled with protonation of cytosine bases in different conformations. We rationalized the pH-dependent dynamics and conformational variability of the i-motif in terms of base pairing and specific loop motions. The human telomeric i-motif is found to acquire various metastable folded conformations at pH values near the p
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- 2022
21. Toward an understanding of the relation between gene regulation and 3D genome organization
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Yi Qin Gao, Hao Tian, Ying Yang, Hui Quan, and Sirui Liu
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Regulation of gene expression ,Applied Mathematics ,Gene regulatory network ,Biology ,Genome ,Biochemistry, Genetics and Molecular Biology (miscellaneous) ,DNA sequencing ,Computer Science Applications ,Chromatin ,Chromosome conformation capture ,CpG site ,Evolutionary biology ,Modeling and Simulation ,Gene ,Genomic organization ,Sequence (medicine) - Abstract
High-order chromatin structure has been shown to play a vital role in gene regulation. Previously we identified two types of sequence domains, CGI (CpG island) forest and CGI prairie, which tend to spatially segregate, but to different extent in different tissues. Here we aim to further quantify the association of domain segregation with gene regulation and therefore differentiation. By means of the published RNA-seq and Hi-C data, we identified tissue-specific genes and quantitatively investigated how their regulation is relevant to chromatin structure. Besides, two types of gene networks were constructed and the association between gene pair co-regulation and genome organization is discussed. We show that compared to forests, tissue-specific genes tend to be enriched in prairies. Highly specific genes also tend to cluster according to their functions in a relatively small number of prairies. Furthermore, tissue-specific forest-prairie contact formation was associated with the regulation of tissue-specific genes, in particular those in the prairie domains, pointing to the important role of gene positioning, in the linear DNA sequence as well as in 3D chromatin structure, in gene regulatory network formation. We investigated how gene regulation is related to genome organization from the perspective of forest-prairie spatial interactions. Since unlike compartments A and B, forest and prairie are identified solely based on sequence properties. Therefore, the simple and uniform framework (forest-prairie domain segregation) provided here can be utilized to further understand the chromatin structure changes as well as the underlying biological significances in different stages, such as tumorgenesis.
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- 2020
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22. The importance of dynamic effects in chemical reactions in condensed phase
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Yao-Kun Lei, Yi Qin Gao, Zhen Zhang, and Jun Zhang
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Materials science ,General Chemical Engineering ,Intermolecular force ,Degrees of freedom (physics and chemistry) ,Solvation ,General Chemistry ,Dissipation ,Biochemistry ,Chemical reaction ,Reaction dynamics ,Chemical physics ,Phase (matter) ,Materials Chemistry ,Specific energy - Abstract
Energy transfer and spatial diffusion are two significant sub-processes in chemical reaction. Traditional rate theory is based on two assumptions: (1) energy transfer is faster than chemical reaction so that specific energy transfer channel is not important. (2) The solvents can respond to the change of solute quickly resulting in equilibrium solvation. Then once system cross the barrier, it will enter the product basin. But when energy transfer is fast enough to distribute the energy into all degrees of freedom according to certain ratio, the specific energy transfer pathways should be considered. Our previous studies have found that the polar functional groups play the major role in the intermolecular energy transfer process. And the energy accumulation and dissipation are completed by the motion with specific frequency. Furthermore, the major energy transfer channel is different in different solutions. Moreover, the length of transition path is very short, leading to the existence of different transient solvation configurations with distinctly different strengths of interaction between solutes and solvents. Consequently, the motion of solvents modulates the reaction dynamics and results in heterogeneous reaction paths. Therefore, the dynamic effects are vital for understanding and controlling the chemical reaction.
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- 2020
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23. Role of Engineered Iron-haem Enzyme in Reactivity and Stereoselectivity of Intermolecular Benzylic C–H Bond Amination
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Hui Gao, Juping Wang, Lijiang Yang, and Yi Qin Gao
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chemistry.chemical_classification ,C h bond ,010405 organic chemistry ,Stereochemistry ,Chemistry ,digestive, oral, and skin physiology ,Intermolecular force ,General Chemistry ,010402 general chemistry ,01 natural sciences ,Catalysis ,0104 chemical sciences ,QM/MM ,Enzyme ,polycyclic compounds ,Reactivity (chemistry) ,Stereoselectivity ,Amination - Abstract
A recent success in which the engineered iron-haem enzymes P411CHA′ aminate the intermolecular benzylic C–H bond with both high efficiency and stereoselectivity solves a long-standing challenge in ...
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- 2020
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24. Expression regulation of genes is linked to their CpG density distributions around transcription start sites
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Hao Tian, Yueying He, Yue Xue, and Yi Qin Gao
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Genes, Essential ,Ecology ,Gene Expression Regulation ,Health, Toxicology and Mutagenesis ,Humans ,CpG Islands ,Plant Science ,DNA Methylation ,Transcription Initiation Site ,Biochemistry, Genetics and Molecular Biology (miscellaneous) - Abstract
The CpG dinucleotide and its methylation behaviors play vital roles in gene regulation. Previous studies have divided genes into several categories based on the CpG intensity around transcription starting sites and found that housekeeping genes tend to possess high CpG density, whereas tissue-specific genes are generally characterized by low CpG density. In this study, we investigated how the CpG density distribution of a gene affects its transcription and regulation pattern. Based on the CpG density distribution around transcription starting site, by means of a semi-supervised neural network we designed, which took data augmentation into account, we divided the human genes into three categories, and genes within each cluster shared similar CpG density distribution. Not only sequence properties, these different clusters exhibited distinctly different structural features, regulatory mechanisms, correlation patterns between the expression level and CpG/TpG density, and expression and epigenetic mark variations during tumorigenesis. For instance, the activation of cluster 3 genes relies more on 3D genome reorganization, compared with cluster 1 and 2 genes, whereas cluster 2 genes showed the strongest correlation between gene expression and H3K27me3. Genes exhibiting uncoupled correlation between gene regulation and histone modifications are mainly in cluster 3. These results emphasized that the usage of epigenetic marks in gene regulation is partially rooted in the sequence property of genes such as their CpG density distribution and explained to some extent why the relation between epigenetic marks and gene expression is controversial.
- Published
- 2021
25. Understanding gene regulatory mechanisms based on gene classification
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Hao Tian, Y. He, Yue Xue, and Yi Qin Gao
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Regulation of gene expression ,CpG site ,Human genome ,Epigenetics ,Computational biology ,Methylation ,Biology ,Gene ,Housekeeping gene ,Genomic organization - Abstract
The CpG dinucleotide and its methylation play vital roles in gene regulation as well as 3D genome organization. Previous studies have divided genes into several categories based on the CpG intensity around transcription starting sites (TSS) and found that housekeeping genes tend to possess high CpG density while tissue-specific genes are generally characterized by low CpG density. In this study, we investigated how the CpG density distribution of a gene affects its transcription and regulation pattern. Based on the CpG density distribution around TSS, the human genes are clearly divided into different categories. Not only sequence properties, these different clusters exhibited distinctly different structural features, regulatory mechanisms, and correlation patterns between expression level and CpG/TpG density. These results emphasized that the usage of epigenetic marks in gene regulation is partially rooted in the sequence property of genes, such as their CpG density distribution.
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- 2021
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26. Author response for 'Computational characterization of domain-segregated 3D chromatin structure and segmented DNA methylation status in carcinogenesis'
- Author
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Yi Qin Gao, Yue Xue, Ling Zhang, Ying Yang, Lu Yang, Sirui Liu, Hong Wu, Hao Tian, Hui Quan, and Haichuan Zhu
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Chemistry ,DNA methylation ,medicine ,Computational biology ,Carcinogenesis ,medicine.disease_cause ,Chromatin ,Domain (software engineering) - Published
- 2021
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27. DNA repair glycosylase hNEIL1 triages damaged bases via competing interaction modes
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Menghao Liu, Weide Xiao, Lulu Liu, Yongchang Yan, Jun Zhang, Xiaoxue Zhang, Hu Zeng, Chenxu Zhu, Yi Qin Gao, and Chengqi Yi
- Subjects
0301 basic medicine ,DNA Repair ,Protein Conformation ,DNA repair ,DNA damage ,Science ,General Physics and Astronomy ,Computational biology ,Molecular dynamics ,Molecular Dynamics Simulation ,medicine.disease_cause ,Article ,General Biochemistry, Genetics and Molecular Biology ,DNA Glycosylases ,Substrate Specificity ,Nucleobase ,Deoxyribonuclease (Pyrimidine Dimer) ,03 medical and health sciences ,Endonuclease ,0302 clinical medicine ,Catalytic Domain ,medicine ,Humans ,A-DNA ,Amino Acid Sequence ,X-ray crystallography ,Base excision repair ,Mutation ,Binding Sites ,Multidisciplinary ,biology ,Chemistry ,DNA ,General Chemistry ,030104 developmental biology ,DNA glycosylase ,030220 oncology & carcinogenesis ,Enzyme mechanisms ,biology.protein ,Triage ,DNA Damage - Abstract
DNA glycosylases must distinguish the sparse damaged sites from the vast expanse of normal DNA bases. However, our understanding of the nature of nucleobase interrogation is still limited. Here, we show that hNEIL1 (human endonuclease VIII-like 1) captures base lesions via two competing states of interaction: an activated state that commits catalysis and base excision repair, and a quarantine state that temporarily separates and protects the flipped base via auto-inhibition. The relative dominance of the two states depends on key residues of hNEIL1 and chemical properties (e.g. aromaticity and hydrophilicity) of flipped bases. Such a DNA repair mechanism allows hNEIL1 to recognize a broad spectrum of DNA damage while keeps potential gratuitous repair in check. We further reveal the molecular basis of hNEIL1 activity regulation mediated by post-transcriptional modifications and provide an example of how exquisite structural dynamics serves for orchestrated enzyme functions., hNEIL1 (human endonuclease VIII-like 1) is a broadly specific DNA glycosylase for base excision repair. Here, the authors show that hNEIL1 can assume activated or triage conformations: the structural basis for the mechanism that enables broad specificity and reduces futile repair of normal bases.
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- 2021
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28. Deep Representation Learning for Complex Free-Energy Landscapes
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Yi Qin Gao, Yao-Kun Lei, Zhen Zhang, Xing Che, Yi Isaac Yang, and Jun Zhang
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Theoretical computer science ,010304 chemical physics ,Computer science ,Inductive bias ,Dimensionality reduction ,010402 general chemistry ,01 natural sciences ,0104 chemical sciences ,0103 physical sciences ,Unsupervised learning ,General Materials Science ,Physical and Theoretical Chemistry ,Representation (mathematics) ,Cluster analysis ,Feature learning ,Parametric statistics ,Curse of dimensionality - Abstract
In this Letter, we analyzed the inductive bias underlying complex free-energy landscapes (FELs) and exploited it to train deep neural networks that yield reduced and clustered representation for the FEL. Our parametric method, called information distilling of metastability (IDM), is end-to-end differentiable and thus scalable to ultralarge data sets. IDM is able to perform clustering in the meantime of reducing the dimensionality. Besides, as an unsupervised learning method, IDM differs from many existing dimensionality reduction and clustering methods in that it requires neither a cherry-picked distance metric nor the ground-true number of clusters defined a priori, and it can be used to unroll and zoom in on the hierarchical FEL with respect to different time scales. Through multiple experiments, we show that IDM can achieve physically meaningful representations that partition the FEL into well-defined metastable states that hence are amenable for downstream tasks such as mechanism analysis and kinetic modeling.
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- 2019
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29. Ice Nucleation of Confined Monolayer Water Conforms to Classical Nucleation Theory
- Author
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Yuheng Zhao, Zhuoran Qiao, and Yi Qin Gao
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Materials science ,Graphene ,Liquid phase ,02 engineering and technology ,021001 nanoscience & nanotechnology ,01 natural sciences ,law.invention ,law ,Chemical physics ,0103 physical sciences ,Monolayer ,Ice nucleus ,General Materials Science ,Classical nucleation theory ,Physical and Theoretical Chemistry ,010306 general physics ,0210 nano-technology ,Supercooling - Abstract
We confirmed that monolayer water confined by parallel graphene sheets spontaneously crystallizes from a structurally and dynamically heterogeneous liquid phase under moderate supercooling via direct molecular dynamics simulation. Square-lattice-like geometric order is observed at the early stage of nucleation and is preserved during the entire nucleus growth process. The diffusion coefficient and free energy profile in the cluster space extracted from a Bayesian trajectory analysis agree well with the classical nucleation theory (CNT) prediction and yield thermodynamic quantities exhibiting linear temperature dependence. The effectiveness of maximum cluster size as the descriptor of ice nucleation dynamics in the CNT framework can be attributed to the dynamical time scale decoupling and strong structural pattern dependence of density fluctuation in the liquid phase.
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- 2019
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30. Interlayer hopping dynamics of bilayer water confined between graphene sheets
- Author
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Zhuoran Qiao, Wen Jun Xie, Xiaoxia Cai, and Yi Qin Gao
- Subjects
Materials science ,Graphene ,Hydrogen bond ,Bilayer ,Dynamics (mechanics) ,General Physics and Astronomy ,02 engineering and technology ,010402 general chemistry ,021001 nanoscience & nanotechnology ,01 natural sciences ,0104 chemical sciences ,Relaxation behavior ,law.invention ,Molecular dynamics ,Chemical physics ,law ,Physical and Theoretical Chemistry ,0210 nano-technology ,Confined water ,Anisotropy - Abstract
The ubiquitous existence of water confined in nano-capillaries is key to fundamental biological and technological applications. Using molecular dynamics simulations, we analyzed the hopping-like interlayer relocation dynamics of bilayer water confined between two parallel graphene sheets. In contrary to the common scheme that relocation is driven by density fluctuations, analysis of the transition path ensemble revealed that interlayer hopping is induced by local hydrogen bond configuration fluctuations coupled with activated consecutive transient angular reorientations. Our results consolidated the anisotropic nature of water relocation under strong ordering, which provided a mechanistic insight into the relaxation behavior at glass-forming water’s fragile-to-strong crossover.
- Published
- 2019
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31. Xponge: A Python package to perform pre- and post-processing of molecular simulations
- Author
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Yijie Xia and Yi Qin Gao
- Published
- 2022
- Full Text
- View/download PDF
32. A perspective on the molecular simulation of DNA from structural and functional aspects
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Lijiang Yang, Manas Mondal, Zhicheng Cai, Yi Qin Gao, and Piya Patra
- Subjects
Regulation of gene expression ,0303 health sciences ,Chemistry ,Sequence (biology) ,Context (language use) ,General Chemistry ,Plasma protein binding ,Computational biology ,010402 general chemistry ,01 natural sciences ,DNA sequencing ,0104 chemical sciences ,Chromatin ,03 medical and health sciences ,chemistry.chemical_compound ,Transcription (biology) ,DNA ,030304 developmental biology - Abstract
As genetic material, DNA not only carries genetic information by sequence, but also affects biological functions ranging from base modification to replication, transcription and gene regulation through its structural and dynamic properties and variations. The motion and structural properties of DNA involved in related biological processes are also multi-scale, ranging from single base flipping to local DNA deformation, TF binding, G-quadruplex and i-motif formation, TAD establishment, compartmentalization and even chromosome territory formation, just to name a few. The sequence-dependent physical properties of DNA play vital role in all these events, and thus it is interesting to examine how simple sequence information affects DNA and the formation of the chromatin structure in these different hierarchical orders. Accordingly, molecular simulations can provide atomistic details of interactions and conformational dynamics involved in different biological processes of DNA, including those inaccessible by current experimental methods. In this perspective, which is mainly based on our recent studies, we provide a brief overview of the atomistic simulations on how the hierarchical structure and dynamics of DNA can be influenced by its sequences, base modifications, environmental factors and protein binding in the context of the protein–DNA interactions, gene regulation and structural organization of chromatin. We try to connect the DNA sequence, the hierarchical structures of DNA and gene regulation., An overview of atomistic simulations on the effect of sequences, base modifications, environmental factors and protein binding on DNA’s hierarchical structure and dynamics in the context of protein–DNA interactions, gene regulation and structural organization of chromatin.
- Published
- 2021
33. Two-step fitness selection for intra-host variations in SARS-CoV-2
- Author
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Jiarui Li, Pengcheng Du, Lijiang Yang, Ju Zhang, Chuan Song, Danying Chen, Yangzi Song, Nan Ding, Mingxi Hua, Kai Han, Rui Song, Wen Xie, Zhihai Chen, Xianbo Wang, Jingyuan Liu, Yanli Xu, Guiju Gao, Qi Wang, Lin Pu, Lin Di, Jie Li, Jinglin Yue, Junyan Han, Xuesen Zhao, Yonghong Yan, Fengting Yu, Angela R. Wu, Fujie Zhang, Yi Qin Gao, Yanyi Huang, Jianbin Wang, Hui Zeng, and Chen Chen
- Subjects
Adult ,Male ,Adolescent ,Genome, Viral ,Polymorphism, Single Nucleotide ,General Biochemistry, Genetics and Molecular Biology ,Article ,Young Adult ,positive selection ,Vaccine Development ,Humans ,Child ,Phylogeny ,intra-host variation ,Aged ,SARS-CoV-2 ,Infant, Newborn ,COVID-19 ,Infant ,Middle Aged ,dynamic genetic divergences ,Child, Preschool ,Host-Pathogen Interactions ,Mutation ,Spike Glycoprotein, Coronavirus ,Female - Abstract
Spontaneous mutations introduce uncertainty into COVID-19 control procedures and vaccine development. Here, we perform spatio-temporal analysis on intra-host single-nucleotide variations (iSNVs) in 402 clinical samples from 170 patients, which reveals an increase in genetic diversity over time post-symptoms onset within individual patients. Nonsynonymous mutations are over-represented in the pool of iSNVs, but underrepresent at the single nucleotide polymorphism (SNP) level, suggesting a two-step fitness selection process: a large number of nonsynonymous substitutions are generated within the host (positive selection), and these substitutions tend to be unfixed as SNPs in population (negative selection). Dynamic iSNVs changes in subpopulations of different gender, age, illness severity and viral shedding time displayed a varied fitness selection process among populations. Taken together, our study highlights iSNVs provide a mutational pool shaping the virus rapid global evolution., Graphical Abstract, The Intra-host variations in SARS-CoV-2 provide a mutational pool shaping the virus rapid global evolution. Here, Li et al. illustrate dynamic changes of iSNVs in a longitudinal cohort, and explored a two-step fitness selection process of within-host viral evolution.
- Published
- 2021
34. Comparison of the Microsolvation of CaX
- Author
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Zhi-You, Wei, Li-Jiang, Yang, Shi-Yan, Gong, Hong-Guang, Xu, Xi-Ling, Xu, Yi Qin, Gao, and Wei-Jun, Zheng
- Abstract
To understand the microsolvation of alkaline-earth dihalides in water and provide information about the dependence of solvation processes on different halides, we investigated CaBr
- Published
- 2021
35. Progressive domain segregation in early embryonic development and underlying correlation to genetic and epigenetic changes
- Author
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Hao Tian, Hui Quan, Yue Xue, Yu Zhang, Sirui Liu, Yi Qin Gao, and Wei Xie
- Subjects
Zygote ,QH301-705.5 ,Sequence dependence ,Embryonic Development ,Ectoderm ,Germ layer ,Biology ,Article ,Epigenesis, Genetic ,epigenetic modification ,medicine ,Animals ,Humans ,Epigenetics ,Biology (General) ,Gene ,Genome ,domain segregation ,Mechanism (biology) ,Embryogenesis ,Gene Expression Regulation, Developmental ,General Medicine ,DNA Methylation ,sequence ,Embryo, Mammalian ,Chromatin ,Cell biology ,medicine.anatomical_structure ,Structural change ,Evolutionary biology ,DNA methylation ,Maternal to zygotic transition ,ZGA and implantation ,Endoderm ,Reprogramming - Abstract
Chromatin undergoes drastic structural organization and epigenetic reprogramming during embryonic development. We present here a consistent view of the chromatin structural change, epigenetic reprogramming, and the corresponding sequence-dependence in both mouse and human embryo development. The two types of domains, identified earlier as forests (CGI-rich domains) and prairies (CGI-poor domains) based on the uneven distribution of CGI in the genome, become spatially segregated during embryonic development, with the exception of zygotic genome activation (ZGA) and implantation, at which point significant domain mixing occurs. Structural segregation largely coincides with DNA methylation and gene expression changes. Genes located in mixed prairie domains show proliferation and ectoderm differentiation-related function in ZGA and implantation, respectively. The chromatin of the ectoderm shows the weakest and the endoderm the strongest domain segregation in germ layers. This chromatin structure difference between different germ layers generally enlarges upon further differentiation. The systematic chromatin structure establishment and its sequence-based segregation strongly suggest the DNA sequence as a possible driving force for the establishment of chromatin 3D structures that profoundly affect the expression profile. Other possible factors correlated with or influencing chromatin structures, including transcription, the germ layers, and the cell cycle, are discussed for an understanding of concerted chromatin structure and epigenetic changes in development.
- Published
- 2021
- Full Text
- View/download PDF
36. Hydration processes of barium chloride: Size-selected anion photoelectron spectroscopy and theoretical calculations of BaCl
- Author
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Zhi-You, Wei, Li-Jiang, Yang, Hong-Guang, Xu, Umar, Farooq, Xi-Ling, Xu, Yi-Qin, Gao, and Wei-Jun, Zheng
- Abstract
In order to understand the hydration processes of BaCl
- Published
- 2020
37. Deep Learning for Variational Multi-Scale Molecular Modeling
- Author
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Jun Zhang, Yaokun Lei, Yi Isaac Yang, and Yi Qin Gao
- Abstract
Molecular simulations are widely applied in the study of chemical and bio-physical systems. However, theaccessible timescales of atomistic simulations are limited, and extracting equilibrium properties of systemscontaining rare events remains challenging. Two distinct strategies are usually adopted in this regard: eithersticking to the atomistic level and performing enhanced sampling, or trading details for speed by leveragingcoarse-grained models. Although both strategies are promising, either of them, if adopted individually,exhibits severe limitations. In this paper we propose a machine-learning approach to ally both strategies sothat simulations on different scales can benefit mutually from their cross-talks: Accurate coarse-grained (CG)models can be inferred from the fine-grained (FG) simulations through deep generative learning; In turn, FGsimulations can be boosted by the guidance of CG models via deep reinforcement learning. Our methoddefines a variational and adaptive training objective which allows end-to-end training of parametricmolecular models using deep neural networks. Through multiple experiments, we show that our method isefficient and flexible, and performs well on challenging chemical and bio-molecular systems.
- Published
- 2020
- Full Text
- View/download PDF
38. Super-resolution Imaging Reveals Spatiotemporal Propagation of Human Replication Foci Mediated by CTCF-organized Chromatin Structures
- Author
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Qian Peter Su, Miao Ding, Yujie Sun, Yi Qin Gao, Yongzheng Li, Rongqin Li, Xiaoliang Sunney Xie, Ziqing W. Zhao, Mengzhu Liu, Luming Meng, and Weiwei Zhang
- Subjects
DNA Replication ,Epigenomics ,CCCTC-Binding Factor ,Multidisciplinary ,DNA replication, chromatin organization, super-resolution microscopy, S-phase, epigenetic environment, spatio-temporal dynamics ,DNA replication ,Biology ,Biological Sciences ,Origin of replication ,Genome ,Chromatin ,Cell biology ,S Phase ,CTCF ,Replication (statistics) ,Directionality ,Humans ,Epigenetics - Abstract
Mammalian DNA replication is initiated at numerous replication origins, which are clustered into thousands of replication domains (RDs) across the genome.However, it remains unclear whether thereplication origins within each RDare activatedstochastically or preferentially near certain chromatin features. To understand how DNA replication in single human cells is regulated at the sub-RD level, we directly visualized and quantitatively characterized the spatio-temporal organization, morphology, andin situepigenetic signatures of individual replication foci (RFi) across S-phase at super-resolution using stochastic optical reconstruction microscopy. Importantly, we revealed a hierarchical radial pattern of RFi propagation dynamics that reverses directionality from early to late S-phase, and is diminished upon caffeine treatment or CTCF knockdown. Together with simulation and bioinformatic analyses, our findings point to a “CTCF-organized REplication Propagation” (CoREP) model, which suggests a non-random selection mechanism for replication activation at the sub-RD level during early S-phase, mediated by CTCF-organized chromatin structures. Collectively, these findings shed critical insights into the key involvement of local epigenetic environment in coordinating DNA replication across the genome, and have broad implications for our conceptualization of the role of multi-scale chromatin architecture in regulating diverse cell nuclear dynamics in space and time.
- Published
- 2020
- Full Text
- View/download PDF
39. Deep Learning for Multi-Scale Molecular Modeling
- Author
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Jun Zhang, Yaokun Lei, Yi Isaac Yang, and Yi Qin Gao
- Abstract
Molecular simulations are widely applied in the study of chemical and bio-physical systems. However, theaccessible timescales of atomistic simulations are limited, and extracting equilibrium properties of systemscontaining rare events remains challenging. Two distinct strategies are usually adopted in this regard: eithersticking to the atomistic level and performing enhanced sampling, or trading details for speed by leveragingcoarse-grained models. Although both strategies are promising, either of them, if adopted individually,exhibits severe limitations. In this paper we propose a machine-learning approach to ally both strategies sothat simulations on different scales can benefit mutually from their cross-talks: Accurate coarse-grained (CG)models can be inferred from the fine-grained (FG) simulations through deep generative learning; In turn, FGsimulations can be boosted by the guidance of CG models via deep reinforcement learning. Our methoddefines a variational and adaptive training objective which allows end-to-end training of parametricmolecular models using deep neural networks. Through multiple experiments, we show that our method isefficient and flexible, and performs well on challenging chemical and bio-molecular systems.
- Published
- 2020
- Full Text
- View/download PDF
40. Reinforcement Learning for Multi-Scale Molecular Modeling
- Author
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Jun Zhang, Yaokun Lei, Yi Isaac Yang, and Yi Qin Gao
- Abstract
Molecular simulations are widely applied in the study of chemical and bio-physical systems of interest. However, the accessible timescales of atomistic simulations are limited, and extracting equilibrium properties of systems containing rare events remains challenging. Two distinct strategies are usually adopted in this regard: either sticking to the atomistic level and performing enhanced sampling, or trading details for speed by leveraging coarse-grained models. Although both strategies are promising, either of them, if adopted individually, exhibits severe limitations. In this paper we propose a machine-learning approach to take advantage of both strategies. In this approach, simulations on different scales are executed simultaneously and benefit mutually from their cross-talks: Accurate coarse-grained (CG) models can be inferred from the fine-grained (FG) simulations; In turn, FG simulations can be boosted by the guidance of CG models. Our method grounds on unsupervised and reinforcement learning, defined by a variational and adaptive training objective, and allows end-to-end training of parametric models. Through multiple experiments, we show that our method is efficient and flexible, and performs well on challenging chemical and bio-molecular systems.
- Published
- 2020
- Full Text
- View/download PDF
41. Hierarchical dinucleotide distribution in genome along evolution and its effect on chromatin packing
- Author
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Zhicheng Cai, Y. He, Yue Xue, Yi Qin Gao, Hui Quan, Ling Zhang, and Sirui Liu
- Subjects
Distribution (number theory) ,Health, Toxicology and Mutagenesis ,Plant Science ,Biology ,Biochemistry, Genetics and Molecular Biology (miscellaneous) ,Genome ,Birds ,Evolution, Molecular ,03 medical and health sciences ,0302 clinical medicine ,Animals ,Humans ,skin and connective tissue diseases ,Phylogeny ,Research Articles ,030304 developmental biology ,Mammals ,0303 health sciences ,Ecology ,Phylogenetic tree ,Sequence Analysis, RNA ,Computational Biology ,Methylation ,DNA Methylation ,Compartmentalization (psychology) ,Chromatin ,CpG site ,Evolutionary biology ,CpG Islands ,sense organs ,030217 neurology & neurosurgery ,Research Article - Abstract
It describes how hierarchical CpG distribution on the genomes of species change in the evolution and the correlation with the chromatin structure., Dinucleotide densities and their distribution patterns vary significantly among species. Previous studies revealed that CpG is susceptible to methylation, enriched at topologically associating domain boundaries and its distribution along the genome correlates with chromatin compartmentalization. However, the multi-scale organizations of CpG in the linear genome, their role in chromatin organization, and how they change along the evolution are only partially understood. By comparing the CpG distribution at different genomic length scales, we quantify the difference between the CpG distributions of different species and evaluate how the hierarchical uneven CpG distribution appears in evolution. The clustering of species based on the CpG distribution is consistent with the phylogenetic tree. Interestingly, we found the CpG distribution and chromatin structure to be correlated in many different length scales, especially for mammals and avians, consistent with the mosaic CpG distribution in the genomes of these species.
- Published
- 2020
- Full Text
- View/download PDF
42. Domain segregated 3D chromatin structure and segmented DNA methylation in carcinogenesis
- Author
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Ying Yang, Yue Xue, Yi Qin Gao, Sirui Liu, Ling Zhang, Hui Quan, and Hao Tian
- Subjects
Chromosome ,Biology ,medicine.disease_cause ,DNA sequencing ,Chromatin ,Cell biology ,chemistry.chemical_compound ,chemistry ,DNA methylation ,medicine ,Epigenetics ,Carcinogenesis ,Gene ,DNA - Abstract
The three-dimensional (3D) chromatin structure, together with DNA methylation and other epigenetic marks, profoundly affects gene expression and displays abnormal behaviors in cancer cells. We elucidated the chromatin architecture remodeling in carcinogenesis from the perspective of spatial interactions between CGI forest and prairie domains, which are two types of megabase-sized domains defined by different sequence features but show distinct epigenetic and transcriptional patterns. DNA sequence strongly affects chromosome spatial interaction, DNA methylation and gene expression. Globally, forests and prairies show enhanced spatial segregation in cancer cells and such structural changes are accordant with the alteration of CGI interactions and domain boundary insulation, which could affect vital cancer-related properties. As the cancer progresses, a gradual increase of the DNA methylation difference between the two types of DNA domains is also observed for many different types of cancers. These observations are consistent with the change of transcriptional level differences of genes in these two domains, suggesting a highly-connected global structural, epigenetic and transcriptional activity changes in carcinogenesis.
- Published
- 2020
- Full Text
- View/download PDF
43. Unnatural Cytosine Bases Recognized as Thymines by DNA Polymerases by the Formation of the Watson-Crick Geometry
- Author
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Hu Zeng, Manas Mondal, Ruyi Song, Jun Zhang, Bo Xia, Menghao Liu, Chenxu Zhu, Bo He, Yi Qin Gao, and Chengqi Yi
- Subjects
0301 basic medicine ,Molecular Structure ,General Chemistry ,DNA ,DNA-Directed DNA Polymerase ,General Medicine ,010402 general chemistry ,01 natural sciences ,Catalysis ,0104 chemical sciences ,03 medical and health sciences ,Cytosine ,030104 developmental biology ,Humans ,Thymine - Abstract
The emergence of unnatural DNA bases provides opportunities to demystify the mechanisms by which DNA polymerases faithfully decode chemical information on the template. It was previously shown that two unnatural cytosine bases (termed "M-fC" and "I-fC"), which are chemical labeling adducts of the epigenetic base 5-formylcytosine, can induce C-to-T transition during DNA amplification. However, how DNA polymerases recognize such unnatural cytosine bases remains enigmatic. Herein, crystal structures of unnatural cytosine bases pairing to dA/dG in the KlenTaq polymerase-host-guest complex system and pairing to dATP in the KlenTaq polymerase active site were determined. Both M-fC and I-fC base pair with dA/dATP, but not with dG, in a Watson-Crick geometry. This study reveals that the formation of the Watson-Crick geometry, which may be enabled by the A-rule, is important for the recognition of unnatural cytosines.
- Published
- 2018
- Full Text
- View/download PDF
44. Microscopic Insight into the Protein Denaturation Action of Urea and Its Methyl Derivatives
- Author
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Bei Ding, Debopreeti Mukherjee, Jianxin Chen, Yi Qin Gao, Feng Gai, and Lijiang Yang
- Subjects
Chemistry ,Stereochemistry ,Tetramethylurea ,Tryptophan ,02 engineering and technology ,Methylation ,010402 general chemistry ,021001 nanoscience & nanotechnology ,01 natural sciences ,Fluorescence spectroscopy ,0104 chemical sciences ,chemistry.chemical_compound ,Molecular dynamics ,Side chain ,Urea ,Molecule ,General Materials Science ,Physical and Theoretical Chemistry ,0210 nano-technology - Abstract
We employ site-specific, linear and nonlinear infrared spectroscopic techniques as well as fluorescence spectroscopy and molecular dynamics simulations to investigate the binding interactions of urea and three of its derivatives, methylurea, 1,3-dimethylurea, and tetramethylurea, with protein aromatic and polar side chains. We find that (1) urea methylation leads to preferential interactions between the cosolvent molecules and aromatic side chains with an affinity that increases with the number of methyl groups; (2) interactions with tetramethylurea cause significant dehydration of aromatic side chains and the effect is most pronounced for tryptophan; and (3) while neither urea nor tetramethylurea shows preferential accumulation around a polar side chain, the number of hydrogen-bond donors around this side chain is significantly decreased in the presence of tetramethylurea. Taken together, our findings suggest that these urea derivatives, especially tetramethylurea, can effectively disrupt hydrophobic interactions in proteins. Additionally, tetramethylurea can promote intramolecular hydrogen-bond formation and hence induce α-helix folding in peptides, as observed.
- Published
- 2018
- Full Text
- View/download PDF
45. The effect of hydration number on the interfacial transport of sodium ions
- Author
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Prokop Hapala, Jing Guo, Bowei Cheng, Duanyun Cao, Ying Jiang, Ji Chen, Limei Xu, Jinbo Peng, Zhili He, Enge Wang, Pavel Jelínek, Wen Jun Xie, Runze Ma, Xin-Zheng Li, and Yi Qin Gao
- Subjects
Multidisciplinary ,Materials science ,Sodium ,chemistry.chemical_element ,02 engineering and technology ,010402 general chemistry ,021001 nanoscience & nanotechnology ,01 natural sciences ,0104 chemical sciences ,Ion ,Molecular dynamics ,chemistry ,Chemical physics ,Ab initio quantum chemistry methods ,Metastability ,Molecule ,Physics::Chemical Physics ,0210 nano-technology ,Quantum tunnelling ,Ion transporter - Abstract
Ion hydration and transport at interfaces are relevant to a wide range of applied fields and natural processes1–5. Interfacial effects are particularly profound in confined geometries such as nanometre-sized channels6–8, where the mechanisms of ion transport in bulk solutions may not apply9,10. To correlate atomic structure with the transport properties of hydrated ions, both the interfacial inhomogeneity and the complex competing interactions among ions, water and surfaces require detailed molecular-level characterization. Here we constructed individual sodium ion (Na+) hydrates on a NaCl(001) surface by progressively attaching single water molecules (one to five) to the Na+ ion using a combined scanning tunnelling microscopy and noncontact atomic force microscopy system. We found that the Na+ ion hydrated with three water molecules diffuses orders of magnitude more quickly than other ion hydrates. Ab initio calculations revealed that such high ion mobility arises from the existence of a metastable state, in which the three water molecules around the Na+ ion can rotate collectively with a rather small energy barrier. This scenario would apply even at room temperature according to our classical molecular dynamics simulations. Our work suggests that anomalously high diffusion rates for specific hydration numbers of ions are generally determined by the degree of symmetry match between the hydrates and the surface lattice. A sodium ion hydrated with three (rather than one, two, four or five) water molecules diffuses orders of magnitude more quickly than the other ion hydrates owing to the interfacial symmetry mismatch.
- Published
- 2018
- Full Text
- View/download PDF
46. CDNs–STING Interaction Mechanism Investigations and Instructions on Design of CDN-Derivatives
- Author
-
Hui Quan, Lijiang Yang, Xing Che, Jun Zhang, and Yi Qin Gao
- Subjects
0301 basic medicine ,010304 chemical physics ,Chemistry ,Mechanism (biology) ,Molecular Dynamics Simulation ,01 natural sciences ,eye diseases ,Surfaces, Coatings and Films ,Dissociation constant ,03 medical and health sciences ,Sting ,030104 developmental biology ,Interferon Type I ,0103 physical sciences ,Materials Chemistry ,Biophysics ,sense organs ,Nucleotides, Cyclic ,Physical and Theoretical Chemistry ,skin and connective tissue diseases ,Cyclic dinucleotides - Abstract
Cyclic dinucleotides (CDNs) present thousand-fold differences of dissociation constants to STING, a pivotal protein in cytosolic dsDNA immunity. To understand how subtle chemical changes in CDNs lead to these substantial variances, a precise ranking of binding affinity is needed. However, the large size and flexibility of CDNs elevate the entropic effect and pose a challenge for this precise prediction. Therefore, in this paper, we developed a new protocol, a combination of selective-integrated tempering sampling of ligands and molecular docking, to take into account the entropic effects originating from extensive ligand configurational space and solvation on binding affinity evaluations. The calculated ranking orders of CDNs and CDN-derivatives to wild type STING and R232H mutant are in agreement with experimental measurements. Further molecular dynamics analysis revealed that the interaction between phosphonate groups and 232R differentiates the binding affinities. The 2'-5' linked phosphonate groups have a larger tendency to form hydrogen bonds with 232R than those with 3'-5' linkages. Moreover, the new protocol identified structural features that enhanced CDNs-STING binding, such as anti-glycosidic bonds and large pro-R distances, which explains the high binding affinity of dithio-RpRp-2'3'-CDA to STING and is expected to provide valuable guidance in the lead-drug optimization.
- Published
- 2018
- Full Text
- View/download PDF
47. Single Mutations Reshape the Structural Correlation Network of the DMXAA–Human STING Complex
- Author
-
Heng Zhang, Xiao-Xia Du, Jun Zhang, Yi Qin Gao, Xiaoxia Cai, Wen Jun Xie, Lijiang Yang, Zhao-Yang Ye, Zhuoran Long, Xiao-Dong Su, and Xing Che
- Subjects
0301 basic medicine ,Mutation ,Molecular Structure ,STING complex ,Chemistry ,Mechanism (biology) ,Entropy ,Xanthones ,Membrane Proteins ,Hydrogen Bonding ,Computational biology ,Molecular Dynamics Simulation ,medicine.disease_cause ,eye diseases ,Surfaces, Coatings and Films ,03 medical and health sciences ,Sting ,030104 developmental biology ,Interaction network ,Structural correlation ,Materials Chemistry ,medicine ,Humans ,Physical and Theoretical Chemistry - Abstract
Subtle changes in protein sequences are able to alter ligand–protein interactions. Unraveling the mechanism of such phenomena is important for understanding ligand–protein interactions, including the DMXAA–STING interaction. DMXAA specifically binds to mouse STING instead of human STING. However, the S162A mutation and a newly discovered E260I mutation endow human STINGAQ with DMXAA sensitivity. Through molecular dynamics simulations, we revealed how these single mutations alter the DMXAA–STING interaction. Compared to mutated systems, structural correlations in the interaction of STINGAQ with DMXAA are stronger, and the correlations are cross-protomers in the dimeric protein. Analyses on correlation coefficients lead to the identification of two key interactions that mediate the strong cross-protomer correlation in the DMXAA–STINGAQ interaction network: DMXAA–267T–162S* and 238R–260E*. These two interactions are partially and totally interrupted by the S162A and E260I mutations, respectively. Moreover, a...
- Published
- 2017
- Full Text
- View/download PDF
48. Simulation Studies of the Self-Assembly of Halogen-Bonded Sierpiński Triangle Fractals
- Author
-
sup> 北京大学化学与分子工程学院,理论与计算化学研究所,北京分子科学国家实验室,北京 ,, Geng Sun, Yi Isaac Yang, Yi Qin Gao, sup> 北京大学,生物动态成像中心,北京 ,, Wen Jun Xie, and Zhen Zhang
- Subjects
Physics ,Pure mathematics ,Fractal ,Halogen ,02 engineering and technology ,Physical and Theoretical Chemistry ,010402 general chemistry ,021001 nanoscience & nanotechnology ,0210 nano-technology ,01 natural sciences ,0104 chemical sciences ,Sierpinski triangle - Published
- 2017
- Full Text
- View/download PDF
49. Structural properties and influence of solvent on the stability of telomeric four-stranded i-motif DNA
- Author
-
Dhananjay Bhattacharyya, Manas Mondal, and Yi Qin Gao
- Subjects
Base pair ,Stacking ,General Physics and Astronomy ,02 engineering and technology ,Molecular Dynamics Simulation ,010402 general chemistry ,01 natural sciences ,chemistry.chemical_compound ,Molecular dynamics ,Cytosine ,Transcription (biology) ,Physical and Theoretical Chemistry ,Nucleotide Motifs ,Base Pairing ,Regulation of gene expression ,Promoter ,Hydrogen Bonding ,DNA ,Telomere ,021001 nanoscience & nanotechnology ,Intercalating Agents ,0104 chemical sciences ,chemistry ,Biophysics ,Solvents ,0210 nano-technology - Abstract
Repetitive cytosine rich i-motif forming sequences are abundant in the telomere, centromere and promoters of several oncogenes and in some instances are known to regulate transcription and gene expression. The in vivo existence of i-motif structures demands further insight into the factors affecting their formation and stability and development of better understanding of their gene regulatory functions. Most prior studies characterizing the conformational dynamics of i-motifs are based on i-motif forming synthetic constructs. Here, we present a systematic study on the stability and structural properties of biologically relevant i-motifs of telomeric and centromeric repeat fragments. Our results based on molecular dynamics simulations and quantum chemical calculations indicate that along with base pairing interactions within the i-motif core the overall folded conformation is associated with the stable C–H⋯O sugar “zippers” in the narrow grooves and structured water molecules along the wide grooves. The stacked geometry of the hemi-protonated cytosine pairs within the i-motif core is mainly governed by the repulsive base stacking interaction. The loop sequence can affect the structural dynamics of the i-motif by altering the loop motion and backbone conformation. Overall this study provides microscopic insight into the i-motif structure that will be helpful to understand the structural aspect of mechanisms of gene regulation by i-motif DNA.
- Published
- 2019
50. Chromatin structure changes during various processes from a DNA sequence view
- Author
-
Yi Qin Gao, Yue Xue, Hui Quan, Ying Yang, Sirui Liu, and Hao Tian
- Subjects
Nucleolus ,Biology ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Structural Biology ,Chromosome Segregation ,Animals ,Humans ,A-DNA ,Molecular Biology ,Transcription factor ,Cellular Senescence ,030304 developmental biology ,0303 health sciences ,Base Sequence ,Chromosome ,Cell Differentiation ,DNA ,Cell cycle ,Chromatin ,Cell biology ,chemistry ,Nuclear lamina ,030217 neurology & neurosurgery - Abstract
Chromatin mainly consists of protein and DNA, and the sequence information of DNA contributes to controlling the spatial structure of chromatin. Genome-wide contact patterns of chromosome at high precision uncover fine structural properties, conductive to exploring underlying mechanisms on structure establishment and function realization for chromatin. In this short review, we describe changes of chromatin structure during various biological processes from a DNA sequence view, with an increase of the overall domain segregation from birth to senescence and establishment of cell identity related cross-domain contacts. Segregation patterns vary with cell stage and genomic distance. Meanwhile, possible effects of cell cycle, temperature, nuclear lamina and nucleolus on chromatin structure are discussed. At last, important roles of transcription factors and other proteins in proper chromatin organization are also discussed.
- Published
- 2019
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