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Molecular Simulation in Modern Chemical Physics

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A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Physical Chemistry".

Deadline for manuscript submissions: closed (31 July 2023) | Viewed by 14499

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Special Issue Editors

Dr. Zhaoxi Sun

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Guest Editor

Beijing National Laboratory for Molecular Sciences, College of Chemistry and Molecular Engineering, Institute of Theoretical and Computational Chemistry, Peking University, Beijing 100871, China
Interests: force field; enhanced sampling; host–guest binding; DNA; ionic liquids; path integral
Special Issues, Collections and Topics in MDPI journals

Dr. Jianzhong Chen

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Guest Editor

School of Science, Shandong Jiaotong University, Jinan 250357, China
Interests: gaussian accelerated dynamics simulations; binding free energy calculations; RNA–ligand identification
Special Issues, Collections and Topics in MDPI journals

Dr. Ya Gao

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Guest Editor

School of Mathematics, Physics and Statistics, Shanghai University of Engineering Science, Shanghai 201620, China
Interests: multiscale molecular dynamics simulation; Gram-negative bacteria; force field; protein–ligand interaction; protein folding

Special Issue Information

Dear Colleagues,

The continuing development of molecular dynamics simulations broadens the applicability of computational modelling from idealized statistical mechanics models to realistic complex systems. Simulation tools are widely employed in modern chemical physics research as a microscopic probe detecting detailed spatial and temporal information. A critical factor determining the quality of the simulation outcome is the accuracy of the employed model. Popular Hamiltonians in current studies ranges from high-level ab initio calculations to atomistic fixed-charge force fields and even coarser united-atom models. Another influencing factor is the validity of the ergodic assumption. The time-scale issue is a longstanding problem hindering the convergence of molecular simulation, especially in high-dimensional systems with elevated (free-)energy barriers among relevant basins. Enhanced sampling techniques or free energy calculations are thus needed in these hard-to-sample cases. A relevant problem in these advanced sampling techniques is the selection of reaction coordinate. Property-regulation protocols (e.g., thermostat) are also crucial in molecular simulations. These molecular dynamics protocols are designed to sample the distribution at the targeted property under the ergodic assumption. Although the Born–Oppenheimer approximation successfully handles a number of practical cases, in systems where nuclear quantum effects are significant (e.g., reaction involving light nuclei), it is necessary to go beyond the classical nuclei treatment with, for example, the extended system approach. Elegant applications of advanced simulation tools provide new insights into practical systems as well as useful feedback on existing techniques, which in turn boosts the development of computational methods.

Recognizing the recent development of novel strategies and pivotal applications in molecular dynamics simulations, Molecules is initiating an open invitation to the theoretical and computational chemistry community to contribute to a Special Issue on ‘Molecular Simulation in Modern Chemical Physics’. As suggested by the title, this Special Issue dedicated to molecular simulation welcomes manuscripts relevant to the simulation technique, covering a diverse set of methods (e.g., free energy calculation, force field development and path integral) and applications (e.g., conformational fluctuations in biomolecular systems, catalyzed chemical reactions and reactive scattering in vacuo).

Dr. Zhaoxi Sun
Dr. Jianzhong Chen
Dr. Ya Gao
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Molecules is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

molecular simulation
thermodynamics
kinetics
conformational fluctuation
force field
enhanced sampling
ab initio calculations
target–ligand identification

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Published Papers (7 papers)

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Research

22 pages, 3910 KiB

Open AccessArticle

Interaction of Macromolecular Chain with Phospholipid Membranes in Solutions: A Dissipative Particle Dynamics Simulation Study

by Yuane Wang, Xuankang Mou, Yongyun Ji, Fan Pan and Shiben Li

Molecules 2023, 28(15), 5790; https://doi.org/10.3390/molecules28155790 - 31 Jul 2023

Viewed by 1227

Abstract

The interaction between macromolecular chains and phospholipid membranes in aqueous solution was investigated using dissipative particle dynamics simulations. Two cases were considered, one in which the macromolecular chains were pulled along parallel to the membrane surfaces and another in which they were pulled vertical to the membrane surfaces. Several parameters, including the radius of gyration, shape factor, particle number, and order parameter, were used to investigate the interaction mechanisms during the dynamics processes by adjusting the pulling force strength of the chains. In both cases, the results showed that the macromolecular chains undergo conformational transitions from a coiled to a rod-like structure. Furthermore, the simulations revealed that the membranes can be damaged and repaired during the dynamic processes. The role of the pulling forces and the adsorption interactions between the chains and membranes differed in the parallel and perpendicular pulling cases. These findings contribute to our understanding of the interaction mechanisms between macromolecules and membranes, and they may have potential applications in biology and medicine. Full article

(This article belongs to the Special Issue Molecular Simulation in Modern Chemical Physics)

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21 pages, 3956 KiB

Open AccessArticle

Binding Mechanism of Inhibitors to Heat Shock Protein 90 Investigated by Multiple Independent Molecular Dynamics Simulations and Prediction of Binding Free Energy

by Fen Yang, Yiwen Wang, Dongliang Yan, Zhongtao Liu, Benzheng Wei, Jianzhong Chen and Weikai He

Molecules 2023, 28(12), 4792; https://doi.org/10.3390/molecules28124792 - 15 Jun 2023

Cited by 12 | Viewed by 1525

Abstract

The heat shock protein (HSP90) has been an import target of drug design in the treatment of human disease. An exploration of the conformational changes in HSP90 can provide useful information for the development of efficient inhibitors targeting HSP90. In this work, multiple independent all-atom molecular dynamics (AAMD) simulations followed by calculations of the molecular mechanics generalized Born surface area (MM-GBSA) were performed to explore the binding mechanism of three inhibitors (W8Y, W8V, and W8S) to HSP90. The dynamics analyses verified that the presence of inhibitors impacts the structural flexibility, correlated movements, and dynamics behavior of HSP90. The results of the MM-GBSA calculations suggest that the selection of GB models and empirical parameters has important influences on the predicted results and verify that van der Waals interactions are the main forces that determine inhibitor–HSP90 binding. The contributions of separate residues to the inhibitor–HSP90 binding process indicate that hydrogen-bonding interactions (HBIs) and hydrophobic interactions play important roles in HSP90–inhibitor identifications. Moreover, residues L34, N37, D40, A41, D79, I82, G83, M84, F124, and T171 are recognized as hot spots of inhibitor–HSP90 binding and provide significant target sites of for the design of drugs related to HSP90. This study aims to contribute to the development of efficient inhibitors that target HSP90 by providing an energy-based and theoretical foundation. Full article

(This article belongs to the Special Issue Molecular Simulation in Modern Chemical Physics)

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23 pages, 4988 KiB

Open AccessArticle

Impacts of Mutations in the P-Loop on Conformational Alterations of KRAS Investigated with Gaussian Accelerated Molecular Dynamics Simulations

by Shuhua Shi, Linqi Zheng, Yonglian Ren and Ziyu Wang

Molecules 2023, 28(7), 2886; https://doi.org/10.3390/molecules28072886 - 23 Mar 2023

Cited by 4 | Viewed by 1884

Abstract

G12 mutations heavily affect conformational transformation and activity of KRAS. In this study, Gaussian accelerated molecular dynamics (GaMD) simulations were performed on the GDP-bound wild-type (WT), G12A, G12D, and G12R KRAS to probe mutation-mediated impacts on conformational alterations of KRAS. The results indicate that three G12 mutations obviously affect the structural flexibility and internal dynamics of the switch domains. The analyses of the free energy landscapes (FELs) suggest that three G12 mutations induce more conformational states of KRAS and lead to more disordered switch domains. The principal component analysis shows that three G12 mutations change concerted motions and dynamics behavior of the switch domains. The switch domains mostly overlap with the binding region of KRAS to its effectors. Thus, the high disorder states and concerted motion changes of the switch domains induced by G12 mutations affect the activity of KRAS. The analysis of interaction network of GDP with KRAS signifies that the instability in the interactions of GDP and magnesium ion with the switch domain SW1 drives the high disordered state of the switch domains. This work is expected to provide theoretical aids for understanding the function of KRAS. Full article

(This article belongs to the Special Issue Molecular Simulation in Modern Chemical Physics)

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25 pages, 5694 KiB

Open AccessArticle

Deciphering Selectivity Mechanism of BRD9 and TAF1(2) toward Inhibitors Based on Multiple Short Molecular Dynamics Simulations and MM-GBSA Calculations

by Lifei Wang, Yan Wang, Yingxia Yu, Dong Liu, Juan Zhao and Lulu Zhang

Molecules 2023, 28(6), 2583; https://doi.org/10.3390/molecules28062583 - 12 Mar 2023

Cited by 6 | Viewed by 1984

Abstract

BRD9 and TAF1(2) have been regarded as significant targets of drug design for clinically treating acute myeloid leukemia, malignancies, and inflammatory diseases. In this study, multiple short molecular dynamics simulations combined with the molecular mechanics generalized Born surface area method were employed to investigate the binding selectivity of three ligands, 67B, 67C, and 69G, to BRD9/TAF1(2) with IC₅₀ values of 230/59 nM, 1400/46 nM, and 160/410 nM, respectively. The computed binding free energies from the MM-GBSA method displayed good correlations with that provided by the experimental data. The results indicate that the enthalpic contributions played a critical factor in the selectivity recognition of inhibitors toward BRD9 and TAF1(2), indicating that 67B and 67C could more favorably bind to TAF1(2) than BRD9, while 69G had better selectivity toward BRD9 over TAF1(2). In addition, the residue-based free energy decomposition approach was adopted to calculate the inhibitor–residue interaction spectrum, and the results determined the gatekeeper (Y106 in BRD9 and Y1589 in TAF1(2)) and lipophilic shelf (G43, F44, and F45 in BRD9 and W1526, P1527, and F1528 in TAF1(2)), which could be identified as hotspots for designing efficient selective inhibitors toward BRD9 and TAF1(2). This work is also expected to provide significant theoretical guidance and insightful molecular mechanisms for the rational designs of efficient selective inhibitors targeting BRD9 and TAF1(2). Full article

(This article belongs to the Special Issue Molecular Simulation in Modern Chemical Physics)

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20 pages, 7586 KiB

Open AccessArticle

3D Conformational Generative Models for Biological Structures Using Graph Information-Embedded Relative Coordinates

by Mingyuan Xu, Weifeng Huang, Min Xu, Jinping Lei and Hongming Chen

Molecules 2023, 28(1), 321; https://doi.org/10.3390/molecules28010321 - 31 Dec 2022

Cited by 5 | Viewed by 2906

Abstract

Developing molecular generative models for directly generating 3D conformation has recently become a hot research area. Here, an autoencoder based generative model was proposed for molecular conformation generation. A unique feature of our method is that the graph information embedded relative coordinate (GIE-RC), satisfying translation and rotation invariance, was proposed as a novel way for encoding molecular three-dimensional structure. Compared with commonly used Cartesian coordinate and internal coordinate, GIE-RC is less sensitive on errors when decoding latent variables to 3D coordinates. By using this method, a complex 3D generation task can be turned into a graph node feature generation problem. Examples were shown that the GIE-RC based autoencoder model can be used for both ligand and peptide conformation generation. Additionally, this model was used as an efficient conformation sampling method to augment conformation data needed in the construction of neural network-based force field. Full article

(This article belongs to the Special Issue Molecular Simulation in Modern Chemical Physics)

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22 pages, 23581 KiB

Open AccessArticle

Design Two Novel Tetrahydroquinoline Derivatives against Anticancer Target LSD1 with 3D-QSAR Model and Molecular Simulation

by Yongtao Xu, Baoyi Fan, Yunlong Gao, Yifan Chen, Di Han, Jiarui Lu, Taigang Liu, Qinghe Gao, John Zenghui Zhang and Meiting Wang

Molecules 2022, 27(23), 8358; https://doi.org/10.3390/molecules27238358 - 30 Nov 2022

Cited by 9 | Viewed by 1994

Abstract

Lysine-specific demethylase 1 (LSD1) is a histone-modifying enzyme, which is a significant target for anticancer drug research. In this work, 40 reported tetrahydroquinoline-derivative inhibitors targeting LSD1 were studied to establish the three-dimensional quantitative structure–activity relationship (3D-QSAR). The established models CoMFA (Comparative Molecular Field [...] Read more.

R_{pred}^{2}

= 0.709)) and CoMSIA (Comparative Molecular Similarity Index Analysis (q² = 0.764,

R_{pred}^{2}

= 0.713)) yielded good statistical and predictive properties. Based on the corresponding contour maps, seven novel tetrahydroquinoline derivatives were designed. For more information, three of the compounds (D1, D4, and Z17) and the template molecule 18x were explored with molecular dynamics simulations, binding free energy calculations by MM/PBSA method as well as the ADME (absorption, distribution, metabolism, and excretion) prediction. The results suggested that D1, D4, and Z17 performed better than template molecule 18x due to the introduction of the amino and hydrophobic groups, especially for the D1 and D4, which will provide guidance for the design of LSD1 inhibitors. Full article

(This article belongs to the Special Issue Molecular Simulation in Modern Chemical Physics)

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16 pages, 6640 KiB

Open AccessArticle

Toxic Effect of Fullerene and Its Derivatives upon the Transmembrane β₂-Adrenergic Receptors

by Longlong Ren, Zhenxiang Jing, Fei Xia, John Zenghui Zhang and Yang Li

Molecules 2022, 27(14), 4562; https://doi.org/10.3390/molecules27144562 - 18 Jul 2022

Cited by 7 | Viewed by 2084

Abstract

Numerous experiments have revealed that fullerene (C₆₀) and its derivatives can bind to proteins and affect their biological functions. In this study, we explored the interaction between fullerine and the β₂-adrenergic receptor (β₂AR). The MD simulation results show that fullerene binds with the extracellular loop 2 (ECL2) and intracellular loop 2 (ICL2) of β₂AR through hydrophobic interactions and π–π stacking interactions. In the C₆₀_in1 trajectory, due to the π–π stacking interactions of fullerene molecules with PHE and PRO residues on ICL2, ICL2 completely flipped towards the fullerene direction and the fullerene moved slowly into the lipid membrane. When five fullerene molecules were placed on the extracellular side, they preferred to stack into a stable fullerene cluster (a deformed tetrahedral aggregate), and had almost no effect on the structure of β₂AR. The hydroxyl groups of fullerene derivatives (C₆₀(OH)_X, X represents the number of hydroxyl groups, X = 4, 8) can form strong hydrogen bonds with the ECL2, helix6, and helix7 of β₂AR. The hydroxyl groups firmly grasp the β₂AR receptor like several claws, blocking the binding entry of ligands. The simulation results show that fullerene and fullerene derivatives may have a significant effect on the local structure of β₂AR, especially the distortion of helix4, but bring about no great changes within the overall structure. It was found that C₆₀ did not compete with ligands for binding sites, but blocked the ligands’ entry into the pocket channel. All the above observations suggest that fullerene and its derivatives exhibit certain cytotoxicity. Full article

(This article belongs to the Special Issue Molecular Simulation in Modern Chemical Physics)

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