Article
Materials Science, Multidisciplinary
Jianfeng Huang, Don McGlinchey, Yi Chen, Daniel McMahon
Summary: Molecular dynamics (MD) simulation is limited by model complexity, but combining it with the Markov state model (MSM) can accelerate computation and improve predictive power. The research demonstrates that applying MSM based on MD microstates can enhance understanding of microstructure evolution in nickel superalloys.
MATERIALS & DESIGN
(2021)
Article
Biochemistry & Molecular Biology
Ying Wang, Mingyu Li, Wenqi Liang, Xinchao Shi, Jigang Fan, Ren Kong, Yaqin Liu, Jian Zhang, Ting Chen, Shaoyong Lu
Summary: This study investigates the activation mechanism of a class B GPCR, human glucagon receptor-GCGR, using molecular dynamics simulations and Markov state models. The study reveals the conformational dynamics and activation process of GCGR and highlights the role of Gs in stabilizing the glucagon binding site and achieving full activation of the receptor.
COMPUTATIONAL AND STRUCTURAL BIOTECHNOLOGY JOURNAL
(2022)
Article
Biochemistry & Molecular Biology
Gao Tu, Qing Liu, Yue Qiu, Elaine Lai-Han Leung, Xiaojun Yao
Summary: This study reveals the mechanisms of drug resistance in KRAS mutant cancers by conducting long time molecular dynamics simulations. The comparative analysis of mutated KRAS bound with and without inhibitors using Markov State Models and 2D-free energy landscapes shows differences in their conformational changes and allosteric signal pathways.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Nanoscience & Nanotechnology
Tianjiao Li, Chenxi Tian, Atieh Moridi, Jingjie Yeo
Summary: Ti-Al-based materials have attracted significant interest in engineering fields due to their remarkable mechanical and chemical properties. However, additive manufacturing and heat treatment of Ti-Al alloys often result in brittleness and defect formation. This study investigates the interfacial dynamics of Ti-Al systems, focusing on the behavior of Ti and Al atoms in the presence of TiAl3 grain boundaries under experimental heat treatment conditions. Molecular dynamics and Markov state modeling techniques reveal the diffusion mechanism and spatial distribution of Al atoms during the formation of TiAl3, providing insights for controlling and optimizing manufacturing processes of these high-performing materials.
ACS APPLIED MATERIALS & INTERFACES
(2023)
Article
Biochemical Research Methods
Hangjin Jiang, Han Li, Wing Hung Wong, Xiaodan Fan
Summary: This paper proposes a new method called Conditional Angle Partition Tree to reveal the hierarchical free energy landscape by correlating local geometric similarity with kinetic similarity. It outperforms existing methods in exploring and understanding the free energy landscape in the benchmark alanine dipeptide MD data. The method also provides more reasonable results and informative insights on the hierarchical structure of the energy landscape in the MD data of Villin HP35.
IEEE-ACM TRANSACTIONS ON COMPUTATIONAL BIOLOGY AND BIOINFORMATICS
(2023)
Article
Chemistry, Multidisciplinary
Emilia P. Barros, Ozlem Demir, Jenaro Soto, Melanie J. Cocco, Rommie E. Amaro
Summary: The study demonstrates the potential significance of mutated p53 in cancer therapy by reactivating it. The mutations induce conformational changes in the important loops L6 and L1 of the p53 protein, suggesting potential new therapeutic targets.
Article
Chemistry, Medicinal
Maohua Yang, Yegen Tang, Jingwei Weng, Zhijun Liu, Wenning Wang
Summary: The D-glucose/D-galactose-binding protein (GGBP) from Escherichia coli is a substrate-binding protein (SBP) associated with sugar transport and chemotaxis. It is also a calcium-binding protein, and the study found that calcium binding can stabilize the open conformation of GGBP, playing an active regulatory role in tuning the conformational distribution of the protein.
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2021)
Article
Chemistry, Physical
Mahdi Ghorbani, Samarjeet Prasad, Jeffery B. Klauda, Bernard R. Brooks
Summary: The study introduces a machine learning method, GMVAE, which can perform dimensionality reduction and clustering of biomolecular conformations effectively. The model shows potential in analyzing the free energy landscape of protein folding, with highly separated clusters corresponding to metastable states during folding.
JOURNAL OF CHEMICAL PHYSICS
(2021)
Article
Pharmacology & Pharmacy
Hao Zhang, Guojun Chu, Gaoming Wang, Min Yao, Shaoyong Lu, Ting Chen
Summary: In this study, extensive molecular dynamics simulations were performed to investigate the conformational changes of the GPR97-G(o) complex in the presence or absence of G(o) palmitoylation. Structural and energetic analyses revealed that palmitoylation of G(o) stabilizes the active conformation of GPR97 and enhances ligand binding affinity. Community network analysis indicated that G(o) palmitoylation strengthens the interactions between G(alpha o) and G(beta gamma) and enhances the coupling between G(o) and GPR97. These findings provide mechanistic insights into the regulation of aGPCRs and have implications for future drug design targeting aGPCRs.
Article
Biochemistry & Molecular Biology
Kaifeng Liu, Fangfang Guo, Yingying Ma, Xiangyu Yu, Xueqi Fu, Wannan Li, Weiwei Han
Summary: This study utilized molecular dynamics simulations and the Markov state model to investigate the inhibitory mechanism of fullerene derivative F-LGPS on spike proteins. The findings revealed that F-LGPS operates at the interface of the receptor-binding domain and the N-terminal domain, and exhibits superior inhibitory effects on the XBB variant.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Biology
Cathrine Bergh, Stephanie A. Heusser, Rebecca Howard, Erik Lindahl
Summary: The study utilized enhanced sampling to simulate the pH-gated channel GLIC and construct Markov state models of gating, revealing differential effects of protonation and mutation on channel states, estimation of open probabilities and transition rates, as well as state- and protonation-dependent symmetrization.
Article
Biochemistry & Molecular Biology
Liuba Mazzanti, Tap Ha-Duong
Summary: The early characterization of drug membrane permeability is crucial for pharmaceutical developments, especially for therapeutic peptides. Further research is needed to understand the relationship between sequence, structure, dynamics, and permeability of peptides for efficient therapeutic peptide design. This study compares two physical models for estimating the permeability coefficient of a benchmark peptide and assesses their accuracy and computational cost.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Microbiology
Edgar Olehnovics, Junqi Yin, Adria Perez, Gianni De Fabritiis, Robert A. Bonomo, Debsindhu Bhowmik, Shozeb Haider
Summary: Class A beta-lactamases are able to rapidly gain broad spectrum catalytic efficiency through minor point mutations. Evolution in these enzymes involves optimizing dynamic phenotypes at different timescales. The stable hydrophobic core in class A beta-lactamases is linked to the structural dynamics of the active site.
FRONTIERS IN MICROBIOLOGY
(2021)
Article
Biochemistry & Molecular Biology
Kazi Lutful Kabir, Buyong Ma, Ruth Nussinov, Amarda Shehu
Summary: This paper investigates the application of Markov State Models (MSM) in the field of molecular dynamics and explores two important aspects in building the models: the selection of structure representation and the application of clustering algorithms. The results suggest that using fewer dimensions and including more structures leads to better models, which contribute to our understanding of antibody dynamics and antibody-antigen recognition.
Article
Multidisciplinary Sciences
Tim Hempel, Mauricio J. del Razo, Christopher T. Lee, Bryn C. Taylor, Rommie E. Amaro, Frank Noe
Summary: In this study, a technique called independent Markov decomposition (IMD) is introduced, which leverages weak coupling between subsystems to compute a global kinetic model without requiring sampling of all combinatorial states of subsystems. It is demonstrated that IMD models can reproduce experimental conductance measurements with significant reduction in sampling compared to a standard approach. The study also proposes a method to find the optimal partition of all-atom protein simulations into weakly coupled subunits.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2021)
Article
Multidisciplinary Sciences
Chu Li, Zhuo Liu, Eshani C. Goonetilleke, Xuhui Huang
Summary: The study uses Markov State Models and transition path theory to elucidate the ensemble pathways of heterogeneous ice nucleation. The results reveal that classical one-step and non-classical two-step nucleation pathways can co-exist at specific temperatures, with favorable conditions for the non-classical pathway. Insights into the mechanisms of heterogeneous ice nucleation are provided, shedding light on rational designs for controlling crystallization processes.
NATURE COMMUNICATIONS
(2021)
Article
Chemistry, Physical
Hanlin Gu, Wei Wang, Siqin Cao, Ilona Christy Unarta, Yuan Yao, Fu Kit Sheong, Xuhui Huang
Summary: The paper presents a new method based on RPnet to cluster microstates into macrostates for analyzing the conformational dynamics of biological macromolecules. Through the reverse-projection scheme and neural network, successful analysis of dynamics of 2D potential, alanine dipeptide, and RNA polymerase was achieved.
PHYSICAL CHEMISTRY CHEMICAL PHYSICS
(2022)
Article
Chemistry, Physical
Siqin Cao, Yunrui Qiu, Ilona C. Unarta, Eshani C. Goonetilleke, Xuhui Huang
Summary: The 3D reference interaction site model with Ion-Dipole Correction (3DRISM-IDC) is proposed to accurately predict the water distributions around negatively charged solute molecules. It significantly outperforms the existing 3DRISM theory in accurately predicting solvation structures and improving the accuracy of hydration free-energy calculation. The 3DRISM-IDC theory shows promise in studying solvation properties for nucleic acids and other biomolecules containing negatively charged functional groups.
JOURNAL OF PHYSICAL CHEMISTRY B
(2022)
Article
Materials Science, Multidisciplinary
Bojun Liu, Yunrui Qiu, Eshani C. Goonetilleke, Xuhui Huang
Summary: Self-assembly is a powerful approach for fabricating advanced materials, but understanding its kinetics at a molecular level is challenging. Kinetic network models based on molecular dynamics simulations have shown potential in elucidating self-assembly pathways. This article discusses challenges in using these models and reviews the recent development of machine learning approaches to address them. It also highlights the potential of these models in molecular self-assembly studies and material design.
Review
Biochemistry & Molecular Biology
Ilona Christy Unarta, Eshani C. Goonetilleke, Dong Wang, Xuhui Huang
Summary: RNA polymerase II (Pol II) incorporates complementary ribonucleotides into the growing RNA chain one at a time and ensures transcriptional fidelity by backtracking and cleaving misincorporated nucleotides. Recent studies have made progress in understanding the catalytic mechanisms of Pol II, including the two-metal-ion mechanism for nucleotide addition and the role of Pol II residues in facilitating the catalysis. Interestingly, Pol II relies on its residues to recognize misincorporated nucleotides during backtracking before cleavage, effectively compartmentalizing its dual catalytic functions using the same active site.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2023)
Article
Chemistry, Physical
Kirill A. Konovalov, Cheng-Guo Wu, Yunrui Qiu, Vijaya Kumar Balakrishnan, Pankaj Singh Parihar, Michael S. O'Connor, Yongna Xing, Xuhui Huang
Summary: Mutations in protein phosphatase 2A (PP2A) disrupt its autoinhibition and phosphorylation-induced activation, leading to intellectual disability and cancer. Allosteric pathway analysis and biochemical experiments reveal that the disease mutant E198K weakens the stabilizing pathways of the regulatory subunit B56d, while the mutant E200K induces exposure of the active site. Remarkably, the allosteric pathways of E198K resemble those in phosphorylation-activated WT, suggesting a conserved mechanism for alleviating autoinhibition.
JOURNAL OF CHEMICAL PHYSICS
(2023)
Article
Chemistry, Multidisciplinary
Siqin Cao, Michael L. L. Kalin, Xuhui Huang
Summary: Integral equation theory (IET) is an effective solvation model that provides computational efficiency and accuracy. We have developed a new software package called EPISOL, which utilizes 3D-RISM calculations to obtain solvation structure and free energies of solute molecules in different solvents. EPISOL features various closures, free energy functionals, and numerical schemes to enhance stability and convergence. It is compatible with AMBER and GROMACS simulation packages and can efficiently handle large biomolecules. EPISOL is a valuable tool for calculating solvation density distributions and solvent free energy in chemical and biological systems.
JOURNAL OF COMPUTATIONAL CHEMISTRY
(2023)
Article
Chemistry, Multidisciplinary
Anthony J. Dominic III, Siqin Cao, Andres Montoya-Castillo, Xuhui Huang
Summary: Conformational changes in biomolecular systems are essential for their function and understanding these changes can have significant implications for drug discovery and bioengineering applications. While Markov state models have provided insights into slow conformational dynamics, this Perspective highlights the importance of incorporating memory effects to improve computational efficiency and accuracy. Various techniques such as Fokker-Planck equations, recurrent neural networks, and generalized master equations, which consider memory effects, are discussed in this article.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2023)
Article
Biochemistry & Molecular Biology
Eric M. M. Kohn, Kirill Konovalov, Christian A. A. Gomez, Gillian N. N. Hoover, Andrew Kai-hei Yik, Xuhui Huang, Jeffrey D. D. Martell
Summary: This study demonstrates the utility of terminal alkynes in improving the binding properties of DNA aptamers to proteins. The terminal alkyne enhances the binding affinity by stabilizing the aptamer-protein interface through noncovalent interactions. This is the first case of terminal alkynes enhancing the binding properties of an aptamer.
ACS CHEMICAL BIOLOGY
(2023)
Article
Chemistry, Physical
Siqin Cao, Yunrui Qiu, Michael L. Kalin, Xuhui Huang
Summary: The generalized master equation (GME) is a powerful method for studying biomolecular dynamics. We present a new method, the Integrative GME (IGME), which analytically solves the GME when the memory kernels have decayed to zero, overcoming the challenges of the quasi Markov State Model (qMSM).
JOURNAL OF CHEMICAL PHYSICS
(2023)
Article
Chemistry, Physical
Bojun Liu, Mingyi Xue, Yunrui Qiu, Kirill A. Konovalov, Michael S. O'Connor, Xuhui Huang
Summary: Identifying slow collective variables (CVs) in self-assembly dynamics is challenging due to permutation and rotational symmetries as well as the out-of-equilibrium nature. In this study, GraphVAMPnets, a combination of graph neural networks and variational Markovian process theory, is utilized to overcome these challenges and identify the slow CVs in self-assembly processes of two systems. The method proves effective in capturing the essential dynamics of self-assembly.
JOURNAL OF CHEMICAL PHYSICS
(2023)
Article
Chemistry, Physical
Yunrui Qiu, Michael S. O'Connor, Mingyi Xue, Bojun Liu, Xuhui Huang
Summary: Conformational changes are crucial in chemical and biological processes, but analyzing complex conformational changes can be challenging due to the vast number of kinetic pathways involved. To address this issue, researchers have developed a path classification algorithm (LPC) that efficiently groups parallel kinetic pathways into distinct metastable path channels, making them easier to comprehend.
JOURNAL OF CHEMICAL THEORY AND COMPUTATION
(2023)
Article
Chemistry, Multidisciplinary
Taylor R. Quinn, Calvin N. Steussy, Brandon E. Haines, Jinping Lei, Wei Wang, Fu Kit Sheong, Cynthia Stauffacher, Xuhui Huang, Per-Ola Norrby, Paul Helquist, Olaf Wiest
Summary: Understanding enzymatic catalysis involves a detailed understanding of the complex interplay of structure and dynamics, which is challenging for both experimental and computational approaches. A novel approach using transition state force fields derived by quantum-guided molecular mechanics allows simulations at the microsecond timescale, enabling prediction of remote dynamic effects on enzyme activity. This approach has been validated experimentally, showing its potential in predicting remote allosteric residues.
Article
Chemistry, Physical
Lu Zhang, Dong Zhang, Xiaowei Wang, Congmin Yuan, Yongfang Li, Xilin Jia, Xin Gao, Hui-Ling Yen, Peter Pak-Hang Cheung, Xuhui Huang
Summary: Remdesivir effectively inhibits SARS-CoV-2 viral RNA replication by interfering with nucleotide addition and proofreading mechanisms, reducing the likelihood of viral replication. The molecular dynamics simulations provide insights into the inhibitory mechanisms of Remdesivir, guiding potential rational designs for new COVID-19 treatments targeting viral replication.
PHYSICAL CHEMISTRY CHEMICAL PHYSICS
(2021)
Article
Biochemistry & Molecular Biology
Zhe Cao, Xiaowei Wang, Xuhui Huang, Ho Yi Mak
Summary: Physical contacts between organelles facilitate the transport of materials within cells, with the endoplasmic reticulum (ER) forming extensive contacts with various organelles, including lipid droplets (LDs).