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Molecular Dynamics Simulations 2.0
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Molecular Dynamics Simulations 2.0

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biophysics".

Deadline for manuscript submissions: closed (30 June 2020) | Viewed by 33573

Special Issue Editors

Dr. Rui M. M. Brito

E-Mail Website
Guest Editor
Chemistry Department and Coimbra Chemistry Centre, Faculty of Science and Technology, University of Coimbra, Coimbra 3004-535, Portugal
Interests: protein structure; stability and folding; protein structure, stability and folding; protein–ligand interactions; rational drug design
Dr. Joaquim Rui Rodrigues

E-Mail Website
Guest Editor
Laboratório Associado LSRE-LCM, Escola Superior de Tecnologia e Gestão, Instituto Politécnico de Leiria, P-2411-901 Leiria, Portugal
Interests: enzymology; protein structure and dynamics; molecular modeling; biomaterials

Special Issue Information

Dear Colleagues,

New developments in X-ray crystallography, fiber diffraction, solid state nuclear magnetic resonance, and cryoelectron microscopy have permitted considerable advances in the determination of biomolecular structures in recent years. However, these structures provide a static view that frequently lack the key data necessary for full understanding of the molecular mechanisms and functions. Molecules are live entities; their atoms are in constant motion, interacting with the environment and other molecules, and a dynamic view is needed to study their behavior. Molecular dynamics (MD) simulations, nowadays, allow for exploration of the time-dependent changes occurring in molecular systems, thus providing paramount information for understanding a wide range of chemical and biological phenomena. In the last decade, advances in algorithms, software, and computer technology regarding high-performance computing and GPU-based processing have resulted in a giant step forward in the MD simulations of complex large molecular systems. In many cases, MD can be viewed as a counterpart to experiments as MD data frequently help interpret in vivo and in vitro results and are invaluable in proposing hypotheses and experiments.

This Special Issue on “Molecular Dynamics Simulations” is open to researchers working with molecular dynamics at any level. We welcome papers addressing methodological or computational developments on force field effects, full atom/coarse-grained calculations, explicit/implicit treatment of solvent, analyses of trajectories, as well as papers reporting applications to diverse molecular systems, interactions, and protein function. Submission of up-to-date review articles is also encouraged.

Dr. Rui M. M. Brito
Dr. Joaquim Rui Rodrigues
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. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. 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

  • dynamic effects in molecules
  • dynamic changes of intermolecular interactions
  • structure–function relationships in proteins
  • protein–ligand interactions
  • nucleic acid–ligand interactions
  • computational modeling of molecular systems
  • drug design

Related Special Issue

Published Papers (6 papers)

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Research

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23 pages, 3557 KiB  
Article
All-Atomic Molecular Dynamic Studies of Human and Drosophila CDK8: Insights into Their Kinase Domains, the LXXLL Motifs, and Drug Binding Site
by Wu Xu, Xiao-Jun Xie, Ali K. Faust, Mengmeng Liu, Xiao Li, Feng Chen, Ashlin A. Naquin, Avery C. Walton, Peter W. Kishbaugh and Jun-Yuan Ji
Int. J. Mol. Sci. 2020, 21(20), 7511; https://doi.org/10.3390/ijms21207511 - 12 Oct 2020
Cited by 6 | Viewed by 2037
Abstract
Cyclin-dependent kinase 8 (CDK8) and its regulatory partner Cyclin C (CycC) play conserved roles in modulating RNA polymerase II (Pol II)-dependent gene expression. To understand the structure and function relations of CDK8, we analyzed the structures of human and Drosophila CDK8 proteins using [...] Read more.
Cyclin-dependent kinase 8 (CDK8) and its regulatory partner Cyclin C (CycC) play conserved roles in modulating RNA polymerase II (Pol II)-dependent gene expression. To understand the structure and function relations of CDK8, we analyzed the structures of human and Drosophila CDK8 proteins using molecular dynamics simulations, combined with functional analyses in Drosophila. Specifically, we evaluated the structural differences between hCDK8 and dCDK8 to predict the effects of the LXXLL motif mutation (AQKAA), the P154L mutations, and drug binding on local structures of the CDK8 proteins. First, we have observed that both the LXXLL motif and the kinase activity of CDK8 are required for the normal larval-to-pupal transition in Drosophila. Second, our molecular dynamic analyses have revealed that hCDK8 has higher hydrogen bond occupation of His149-Asp151 and Asp151-Asn156 than dCDK8. Third, the substructure of Asp282, Phe283, Arg285, Thr287 and Cys291 can distinguish human and Drosophila CDK8 structures. In addition, there are two hydrogen bonds in the LXXLL motif: a lower occupation between L312 and L315, and a relatively higher occupation between L312 and L316. Human CDK8 has higher hydrogen bond occupation between L312 and L316 than dCDK8. Moreover, L312, L315 and L316 in the LXXLL motif of CDK8 have the specific pattern of hydrogen bonds and geometries, which could be crucial for the binding to nuclear receptors. Furthermore, the P154L mutation dramatically decreases the hydrogen bond between L312 and L315 in hCDK8, but not in dCDK8. The mutations of P154L and AQKAA modestly alter the local structures around residues 154. Finally, we identified the inhibitor-induced conformational changes of hCDK8, and our results suggest a structural difference in the drug-binding site between hCDK8 and dCDK8. Taken together, these results provide the structural insights into the roles of the LXXLL motif and the kinase activity of CDK8 in vivo. Full article
(This article belongs to the Special Issue Molecular Dynamics Simulations 2.0)
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10 pages, 1917 KiB  
Article
Molecular Dynamics Simulation and Kinetic Study of Fluoride Binding to V21C/V66C Myoglobin with a Cytoglobin-like Disulfide Bond
by Lu-Lu Yin, Jia-Kun Xu, Xiao-Juan Wang, Shu-Qin Gao and Ying-Wu Lin
Int. J. Mol. Sci. 2020, 21(7), 2512; https://doi.org/10.3390/ijms21072512 - 04 Apr 2020
Cited by 3 | Viewed by 2883
Abstract
Protein design is able to create artificial proteins with advanced functions, and computer simulation plays a key role in guiding the rational design. In the absence of structural evidence for cytoglobin (Cgb) with an intramolecular disulfide bond, we recently designed a de novo [...] Read more.
Protein design is able to create artificial proteins with advanced functions, and computer simulation plays a key role in guiding the rational design. In the absence of structural evidence for cytoglobin (Cgb) with an intramolecular disulfide bond, we recently designed a de novo disulfide bond in myoglobin (Mb) based on structural alignment (i.e., V21C/V66C Mb double mutant). To provide deep insight into the regulation role of the Cys21-Cys66 disulfide bond, we herein perform molecular dynamics (MD) simulation of the fluoride–protein complex by using a fluoride ion as a probe, which reveals detailed interactions of the fluoride ion in the heme distal pocket, involving both the distal His64 and water molecules. Moreover, we determined the kinetic parameters of fluoride binding to the double mutant. The results agree with the MD simulation and show that the formation of the Cys21-Cys66 disulfide bond facilitates both fluoride binding to and dissociating from the heme iron. Therefore, the combination of theoretical and experimental studies provides valuable information for understanding the structure and function of heme proteins, as regulated by a disulfide bond. This study is thus able to guide the rational design of artificial proteins with tunable functions in the future. Full article
(This article belongs to the Special Issue Molecular Dynamics Simulations 2.0)
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15 pages, 12450 KiB  
Article
Computational Study on the Effect of Inactivating/Activating Mutations on the Inhibition of MEK1 by Trametinib
by Jingxuan Zhu, Congcong Li, Hengzheng Yang, Xiaoqing Guo, Tianci Huang and Weiwei Han
Int. J. Mol. Sci. 2020, 21(6), 2167; https://doi.org/10.3390/ijms21062167 - 21 Mar 2020
Cited by 9 | Viewed by 3226
Abstract
Activation of the mitogen-activated protein kinase (MAPK) signaling pathway regulated by human MAP kinase 1 (MEK1) is associated with the carcinogenesis and progression of numerous cancers. In addition, two active mutations (P124S and E203K) have been reported to enhance the activity of MEK1, [...] Read more.
Activation of the mitogen-activated protein kinase (MAPK) signaling pathway regulated by human MAP kinase 1 (MEK1) is associated with the carcinogenesis and progression of numerous cancers. In addition, two active mutations (P124S and E203K) have been reported to enhance the activity of MEK1, thereby eventually leading to the tumorigenesis of cancer. Trametinib is an MEK1 inhibitor for treating EML4-ALK-positive, EGFR-activated, and KRAS-mutant lung cancers. Therefore, in this study, molecular docking and molecular dynamic (MD) simulations were performed to explore the effects of inactive/active mutations (A52V/P124S and E203K) on the conformational changes of MEK1 and the changes in the interaction of MEK1 with trametinib. Moreover, steered molecular dynamic (SMD) simulations were further utilized to compare the dissociation processes of trametinib from the wild-type (WT) MEK1 and two active mutants (P124S and E203K). As a result, trametinib had stronger interactions with the non-active MEK1 (WT and A52V mutant) than the two active mutants (P124S and E203K). Moreover, two active mutants may make the allosteric channel of MEK1 wider and shorter than that of the non-active types (WT and A52V mutant). Hence, trametinib could dissociate from the active mutants (P124S and E203K) more easily compared with the WT MEK1. In summary, our theoretical results demonstrated that the active mutations may attenuate the inhibitory effects of MEK inhibitor (trametinib) on MEK1, which could be crucial clues for future anti-cancer treatment. Full article
(This article belongs to the Special Issue Molecular Dynamics Simulations 2.0)
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22 pages, 7204 KiB  
Article
Structural and Dynamic Characterizations Highlight the Deleterious Role of SULT1A1 R213H Polymorphism in Substrate Binding
by Raju Dash, Md. Chayan Ali, Nayan Dash, Md. Abul Kalam Azad, S. M. Zahid Hosen, Md. Abdul Hannan and Il Soo Moon
Int. J. Mol. Sci. 2019, 20(24), 6256; https://doi.org/10.3390/ijms20246256 - 11 Dec 2019
Cited by 48 | Viewed by 6419
Abstract
Sulfotransferase 1A1 (SULT1A1) is responsible for catalyzing various types of endogenous and exogenous compounds. Accumulating data indicates that the polymorphism rs9282861 (R213H) is responsible for inefficient enzymatic activity and associated with cancer progression. To characterize the detailed functional consequences of this mutation behind [...] Read more.
Sulfotransferase 1A1 (SULT1A1) is responsible for catalyzing various types of endogenous and exogenous compounds. Accumulating data indicates that the polymorphism rs9282861 (R213H) is responsible for inefficient enzymatic activity and associated with cancer progression. To characterize the detailed functional consequences of this mutation behind the loss-of-function of SULT1A1, the present study deployed molecular dynamics simulation to get insights into changes in the conformation and binding energy. The dynamics scenario of SULT1A1 in both wild and mutated types as well as with and without ligand showed that R213H induced local conformational changes, especially in the substrate-binding loop rather than impairing overall stability of the protein structure. The higher conformational changes were observed in the loop3 (residues, 235–263), turning loop conformation to A-helix and B-bridge, which ultimately disrupted the plasticity of the active site. This alteration reduced the binding site volume and hydrophobicity to decrease the binding affinity of the enzyme to substrates, which was highlighted by the MM-PBSA binding energy analysis. These findings highlight the key insights of structural consequences caused by R213H mutation, which would enrich the understanding regarding the role of SULT1A1 mutation in cancer development and also xenobiotics management to individuals in the different treatment stages. Full article
(This article belongs to the Special Issue Molecular Dynamics Simulations 2.0)
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23 pages, 2686 KiB  
Article
Molecular Dynamics Simulation Framework to Probe the Binding Hypothesis of CYP3A4 Inhibitors
by Yusra Sajid Kiani, Kara E. Ranaghan, Ishrat Jabeen and Adrian J. Mulholland
Int. J. Mol. Sci. 2019, 20(18), 4468; https://doi.org/10.3390/ijms20184468 - 10 Sep 2019
Cited by 21 | Viewed by 4369
Abstract
The Cytochrome P450 family of heme-containing proteins plays a major role in catalyzing phase I metabolic reactions, and the CYP3A4 subtype is responsible for the metabolism of many currently marketed drugs. Additionally, CYP3A4 has an inherent affinity for a broad spectrum of structurally [...] Read more.
The Cytochrome P450 family of heme-containing proteins plays a major role in catalyzing phase I metabolic reactions, and the CYP3A4 subtype is responsible for the metabolism of many currently marketed drugs. Additionally, CYP3A4 has an inherent affinity for a broad spectrum of structurally diverse chemical entities, often leading to drug–drug interactions mediated by the inhibition or induction of the metabolic enzyme. The current study explores the binding of selected highly efficient CYP3A4 inhibitors by docking and molecular dynamics (MD) simulation protocols and their binding free energy calculated using the WaterSwap method. The results indicate the importance of binding pocket residues including Phe57, Arg105, Arg106, Ser119, Arg212, Phe213, Thr309, Ser312, Ala370, Arg372, Glu374, Gly481 and Leu483 for interaction with CYP3A4 inhibitors. The residue-wise decomposition of the binding free energy from the WaterSwap method revealed the importance of binding site residues Arg106 and Arg372 in the stabilization of all the selected CYP3A4-inhibitor complexes. The WaterSwap binding energies were further complemented with the MM(GB/PB)SA results and it was observed that the binding energies calculated by both methods do not differ significantly. Overall, our results could guide towards the use of multiple computational approaches to achieve a better understanding of CYP3A4 inhibition, subsequently leading to the design of highly specific and efficient new chemical entities with suitable ADMETox properties and reduced side effects. Full article
(This article belongs to the Special Issue Molecular Dynamics Simulations 2.0)
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Review

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20 pages, 1124 KiB  
Review
Advances in Molecular Dynamics Simulations and Enhanced Sampling Methods for the Study of Protein Systems
by Raudah Lazim, Donghyuk Suh and Sun Choi
Int. J. Mol. Sci. 2020, 21(17), 6339; https://doi.org/10.3390/ijms21176339 - 01 Sep 2020
Cited by 83 | Viewed by 13628
Abstract
Molecular dynamics (MD) simulation is a rigorous theoretical tool that when used efficiently could provide reliable answers to questions pertaining to the structure-function relationship of proteins. Data collated from protein dynamics can be translated into useful statistics that can be exploited to sieve [...] Read more.
Molecular dynamics (MD) simulation is a rigorous theoretical tool that when used efficiently could provide reliable answers to questions pertaining to the structure-function relationship of proteins. Data collated from protein dynamics can be translated into useful statistics that can be exploited to sieve thermodynamics and kinetics crucial for the elucidation of mechanisms responsible for the modulation of biological processes such as protein-ligand binding and protein-protein association. Continuous modernization of simulation tools enables accurate prediction and characterization of the aforementioned mechanisms and these qualities are highly beneficial for the expedition of drug development when effectively applied to structure-based drug design (SBDD). In this review, current all-atom MD simulation methods, with focus on enhanced sampling techniques, utilized to examine protein structure, dynamics, and functions are discussed. This review will pivot around computer calculations of protein-ligand and protein-protein systems with applications to SBDD. In addition, we will also be highlighting limitations faced by current simulation tools as well as the improvements that have been made to ameliorate their efficiency. Full article
(This article belongs to the Special Issue Molecular Dynamics Simulations 2.0)
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