Special Issue "Molecular Dynamics Modeling and Simulation"

A special issue of Processes (ISSN 2227-9717). This special issue belongs to the section "Biological Processes and Systems".

Deadline for manuscript submissions: 10 February 2023 | Viewed by 18743

Special Issue Editors

Dr. Outi Salo-Ahen
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Guest Editor
Pharmaceutical Sciences and Structural Bioinformatics Laboratory, Faculty of Science and Engineering, Abo Akademi University, Biocity, Tykistökatu 6A, FI 20520 Turku, Finland
Interests: computer-aided drug design; molecular dynamics simulations; anti-virulence agents; antibacterials; natural compounds
Special Issues, Collections and Topics in MDPI journals
Dr. Parthiban Marimuthu
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Guest Editor
Structural Bioinformatics Laboratory, Biochemistry, Faculty of Science and Engineering, Abo Akademi University, Biocity, Tykistökatu 6A, FI 20520 Turku, Finland
Interests: computational chemistry; modeling and simulation; structure–activity relationship; virtual screening; protein-protein interactions; protein interaction networks; metadynamics

Special Issue Information

Dear Colleagues,

Understanding the dynamic interactions of molecules is fundamental in material and life sciences. For example, physiological or pathological protein–protein interactions or interactions between drugs and their biological target molecules are of special interest for drug development. In pharmaceutical formulations and drug delivery systems, insight into the molecular interactions of the drug with water and excipients gives valuable information on the properties of the formulation, or studying the dynamics and interactions of biological lipid bilayers can give understanding to many important biological processes. Molecular dynamics (MD) modeling is a powerful approach that can be used to simulate molecular motions and interactions over a period of time. In recent years, state-of-the-art computational platforms and advanced MD methods have made it possible to provide plausible explanations for various biological events, as well as predicting drug binding kinetics or material properties, thus reducing the need for tedious and expensive experimental procedures.

The aim of this Special Issue is to present a contemporary overview of the application of MD simulations in material and life sciences, especially in the context of drug discovery and development. Original research papers and short communications, as well as review articles that address the theoretical and methodological aspects of MD simulations, are all welcome. The submission of articles covering the topics listed below are particularly encouraged.

Dr. Outi Salo-Ahen
Dr. Parthiban Marimuthu
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. Processes is an international peer-reviewed open access monthly 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 2000 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

  • Induced-fit binding
  • Free energy estimation
  • QM/MM simulations
  • Enhanced sampling
  • Cryptic binding pockets
  • Biological networks
  • Steered or targeted molecular dynamics
  • Drug-polymer interactions
  • Drug-nanoparticle interactions
  • Biological membranes
  • Peptide vaccines

Published Papers (7 papers)

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Research

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Article
Explicit-pH Coarse-Grained Molecular Dynamics Simulations Enable Insights into Restructuring of Intestinal Colloidal Aggregates with Permeation Enhancers
Processes 2022, 10(1), 29; https://doi.org/10.3390/pr10010029 - 24 Dec 2021
Cited by 2 | Viewed by 1156
Abstract
Permeation enhancers (PEs) can increase the bioavailability of drugs. The mechanisms of action of these PEs are complex, but, typically, when used for oral administration, they can transiently induce the alteration of trans- and paracellular pathways, including increased solubilization and membrane fluidity, or [...] Read more.
Permeation enhancers (PEs) can increase the bioavailability of drugs. The mechanisms of action of these PEs are complex, but, typically, when used for oral administration, they can transiently induce the alteration of trans- and paracellular pathways, including increased solubilization and membrane fluidity, or the opening of the tight junctions. To elucidate these mechanistic details, it is important to understand the aggregation behavior of not only the PEs themselves but also other molecules already present in the intestine. Aggregation processes depend critically on, among other factors, the charge state of ionizable chemical groups, which is affected by the pH of the system. In this study, we used explicit-pH coarse-grained molecular dynamics simulations to investigate the aggregation behavior and pH dependence of two commonly used PEs—caprate and SNAC—together with other components of fasted- and fed-state simulated intestinal fluids. We also present and validate a coarse-grained molecular topology for the bile salt taurocholate suitable for the Martini3 force-field. Our results indicate an increase in the number of free molecules as a function of the system pH and for each combination of FaSSIF/FeSSIF and PEs. In addition, there are differences between caprate and SNAC, which are rationalized based on their different molecular structures and critical micelle concentrations. Full article
(This article belongs to the Special Issue Molecular Dynamics Modeling and Simulation)
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Article
Interactive Mechanism of Potential Inhibitors with Glycosyl for SARS-CoV-2 by Molecular Dynamics Simulation
Processes 2021, 9(10), 1749; https://doi.org/10.3390/pr9101749 - 29 Sep 2021
Viewed by 598
Abstract
Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is a type of Ribonucleic Acid (RNA) coronavirus and it has infected and killed many people around the world. It is reported that the receptor binding domain of the spike protein (S_RBD) of the SARS-CoV-2 virus [...] Read more.
Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is a type of Ribonucleic Acid (RNA) coronavirus and it has infected and killed many people around the world. It is reported that the receptor binding domain of the spike protein (S_RBD) of the SARS-CoV-2 virus is responsible for attachment to human angiotensin converting enzyme II (ACE2). Many researchers are attempting to search potential inhibitors for fighting SARS-CoV-2 infection using theoretical or experimental methods. In terms of experimental and theoretical research, Cefuroxime, Erythromycin, Lincomycin and Ofloxacin are the potential inhibitors of SARS-CoV-2. However, the interactive mechanism of the protein SARS-CoV-2 and the inhibitors are still elusive. Here, we investigated the interactions between S_RBD and the inhibitors using molecular dynamics (MD) simulations. Interestingly, we found that there are two binding sites of S_RBD for the four small molecules. In addition, our analysis also illustrated that hydrophobic and π-π stacking interactions play crucial roles in the interactions between S_RBD and the small molecules. In our work, we also found that small molecules with glycosyl group have more effect on the conformation of S_RBD than other inhibitors, and they are also potential inhibitors for the genetic variants of SARS-CoV-2. This study provides in silico-derived mechanistic insights into the interactions of S_RBD and inhibitors, which may provide new clues for fighting SARS-CoV-2 infection. Full article
(This article belongs to the Special Issue Molecular Dynamics Modeling and Simulation)
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Article
Protonation Dynamics in the K-Channel of Cytochrome c Oxidase Estimated from Molecular Dynamics Simulations
Processes 2021, 9(2), 265; https://doi.org/10.3390/pr9020265 - 29 Jan 2021
Viewed by 955
Abstract
Proton transfer reactions are one of the most fundamental processes in biochemistry. We present a simplistic approach for estimating proton transfer probabilities in a membrane protein, cytochrome c oxidase. We combine short molecular dynamics simulations at discrete protonation states with a Monte Carlo [...] Read more.
Proton transfer reactions are one of the most fundamental processes in biochemistry. We present a simplistic approach for estimating proton transfer probabilities in a membrane protein, cytochrome c oxidase. We combine short molecular dynamics simulations at discrete protonation states with a Monte Carlo approach to exchange between those states. Requesting for a proton transfer the existence of a hydrogen-bonded connection between the two source and target residues of the exchange, restricts the acceptance of transfers to only those in which a proton-relay is possible. Together with an analysis of the hydrogen-bonded connectivity in one of the proton-conducting channels of cytochrome c oxidase, this approach gives insight into the protonation dynamics of the hydrogen-bonded networks. The connectivity and directionality of the networks are coupled to the conformation of an important protein residue in the channel, K362, rendering proton transfer in the entire channel feasible in only one of the two major conformations. Proton transport in the channel can thus be regulated by K362 not only through its possible role as a proton carrier itself, but also by allowing or preventing proton transport via water residues. Full article
(This article belongs to the Special Issue Molecular Dynamics Modeling and Simulation)
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Article
Structural Influence and Interactive Binding Behavior of Dopamine and Norepinephrine on the Greek-Key-Like Core of α-Synuclein Protofibril Revealed by Molecular Dynamics Simulations
Processes 2019, 7(11), 850; https://doi.org/10.3390/pr7110850 - 13 Nov 2019
Cited by 1 | Viewed by 1073
Abstract
The pathogenesis of Parkinson’s disease (PD) is closely associated with the aggregation of α-synuclein (αS) protein. Finding the effective inhibitors of αS aggregation has been considered as the primary therapeutic strategy for PD. Recent studies reported that two neurotransmitters, dopamine (DA) and norepinephrine [...] Read more.
The pathogenesis of Parkinson’s disease (PD) is closely associated with the aggregation of α-synuclein (αS) protein. Finding the effective inhibitors of αS aggregation has been considered as the primary therapeutic strategy for PD. Recent studies reported that two neurotransmitters, dopamine (DA) and norepinephrine (NE), can effectively inhibit αS aggregation and disrupt the preformed αS fibrils. However, the atomistic details of αS-DA/NE interaction remain unclear. Here, using molecular dynamics simulations, we investigated the binding behavior of DA/NE molecules and their structural influence on αS44–96 (Greek-key-like core of full length αS) protofibrillar tetramer. Our results showed that DA/NE molecules destabilize αS protofibrillar tetramer by disrupting the β-sheet structure and destroying the intra- and inter-peptide E46–K80 salt bridges, and they can also destroy the inter-chain backbone hydrogen bonds. Three binding sites were identified for both DA and NE molecules interacting with αS tetramer: T54–T72, Q79–A85, and F94–K96, and NE molecules had a stronger binding capacity to these sites than DA. The binding of DA/NE molecules to αS tetramer is dominantly driven by electrostatic and hydrogen bonding interactions. Through aromatic π-stacking, DA and NE molecules can bind to αS protofibril interactively. Our work reveals the detailed disruptive mechanism of protofibrillar αS oligomer by DA/NE molecules, which is helpful for the development of drug candidates against PD. Given that exercise as a stressor can stimulate DA/NE secretion and elevated levels of DA/NE could delay the progress of PD, this work also enhances our understanding of the biological mechanism by which exercise prevents and alleviates PD. Full article
(This article belongs to the Special Issue Molecular Dynamics Modeling and Simulation)
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Article
Study of the Lamellar and Micellar Phases of Pluronic F127: A Molecular Dynamics Approach
Processes 2019, 7(9), 606; https://doi.org/10.3390/pr7090606 - 07 Sep 2019
Cited by 3 | Viewed by 2956
Abstract
In this work, we analyzed the behavior of Pluronic F127 through molecular dynamics simulations at the coarse-grain level, focusing on the micellar and lamellar phases. To this aim, two initial polymer conformations were considered, S-shape and U-shape, for both simulated phases. Through the [...] Read more.
In this work, we analyzed the behavior of Pluronic F127 through molecular dynamics simulations at the coarse-grain level, focusing on the micellar and lamellar phases. To this aim, two initial polymer conformations were considered, S-shape and U-shape, for both simulated phases. Through the simulations, we were able to examine the structural and mechanical properties that are difficult to access through experiments. Since no transition between S and U shapes was observed in our simulations, we inferred that all single co-polymers had memory of their initial configuration. Nevertheless, most copolymers had a more complex amorphous structure, where hydrophilic beads were part of the lamellar-like core. Finally, an overall comparison of the micellar a lamellar phases showed that the lamellar thickness was in the same order of magnitude as the micelle diameter (approx. 30 nm). Therefore, high micelle concentration could lead to lamellar formation. With this new information, we could understand lamellae as orderly packed micelles. Full article
(This article belongs to the Special Issue Molecular Dynamics Modeling and Simulation)
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Article
Investigating the Molecular Basis of N-Substituted 1-Hydroxy-4-Sulfamoyl-2-Naphthoate Compounds Binding to Mcl1
Processes 2019, 7(4), 224; https://doi.org/10.3390/pr7040224 - 19 Apr 2019
Cited by 3 | Viewed by 1870
Abstract
Myeloid cell leukemia-1 (Mcl1) is an anti–apoptotic protein that has gained considerable attention due to its overexpression activity prevents cell death. Therefore, a potential inhibitor that specifically targets Mcl1 with higher binding affinity is necessary. Recently, a series of N-substituted 1-hydroxy-4-sulfamoyl-2-naphthoate compounds [...] Read more.
Myeloid cell leukemia-1 (Mcl1) is an anti–apoptotic protein that has gained considerable attention due to its overexpression activity prevents cell death. Therefore, a potential inhibitor that specifically targets Mcl1 with higher binding affinity is necessary. Recently, a series of N-substituted 1-hydroxy-4-sulfamoyl-2-naphthoate compounds was reported that targets Mcl1, but its binding mechanism remains unexplored. Here, we attempted to explore the molecular mechanism of binding to Mcl1 using advanced computational approaches: pharmacophore-based 3D-QSAR, docking, and MD simulation. The selected pharmacophore—NNRRR—yielded a statistically significant 3D-QSAR model containing high confidence scores (R2 = 0.9209, Q2 = 0.8459, and RMSE = 0.3473). The contour maps—comprising hydrogen bond donor, hydrophobic, negative ionic and electron withdrawal effects—from our 3D-QSAR model identified the favorable regions crucial for maximum activity. Furthermore, the external validation of the selected model using enrichment and decoys analysis reveals a high predictive power. Also, the screening capacity of the selected model had scores of 0.94, 0.90, and 8.26 from ROC, AUC, and RIE analysis, respectively. The molecular docking of the highly active compound—C40; 4-(N-benzyl-N-(4-(4-chloro-3,5-dimethylphenoxy) phenyl) sulfamoyl)-1-hydroxy-2-naphthoate—predicted the low-energy conformational pose, and the MD simulation revealed crucial details responsible for the molecular mechanism of binding with Mcl1. Full article
(This article belongs to the Special Issue Molecular Dynamics Modeling and Simulation)
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Review

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Review
Molecular Dynamics Simulations in Drug Discovery and Pharmaceutical Development
Processes 2021, 9(1), 71; https://doi.org/10.3390/pr9010071 - 30 Dec 2020
Cited by 37 | Viewed by 8373
Abstract
Molecular dynamics (MD) simulations have become increasingly useful in the modern drug development process. In this review, we give a broad overview of the current application possibilities of MD in drug discovery and pharmaceutical development. Starting from the target validation step of the [...] Read more.
Molecular dynamics (MD) simulations have become increasingly useful in the modern drug development process. In this review, we give a broad overview of the current application possibilities of MD in drug discovery and pharmaceutical development. Starting from the target validation step of the drug development process, we give several examples of how MD studies can give important insights into the dynamics and function of identified drug targets such as sirtuins, RAS proteins, or intrinsically disordered proteins. The role of MD in antibody design is also reviewed. In the lead discovery and lead optimization phases, MD facilitates the evaluation of the binding energetics and kinetics of the ligand-receptor interactions, therefore guiding the choice of the best candidate molecules for further development. The importance of considering the biological lipid bilayer environment in the MD simulations of membrane proteins is also discussed, using G-protein coupled receptors and ion channels as well as the drug-metabolizing cytochrome P450 enzymes as relevant examples. Lastly, we discuss the emerging role of MD simulations in facilitating the pharmaceutical formulation development of drugs and candidate drugs. Specifically, we look at how MD can be used in studying the crystalline and amorphous solids, the stability of amorphous drug or drug-polymer formulations, and drug solubility. Moreover, since nanoparticle drug formulations are of great interest in the field of drug delivery research, different applications of nano-particle simulations are also briefly summarized using multiple recent studies as examples. In the future, the role of MD simulations in facilitating the drug development process is likely to grow substantially with the increasing computer power and advancements in the development of force fields and enhanced MD methodologies. Full article
(This article belongs to the Special Issue Molecular Dynamics Modeling and Simulation)
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