All-Atom MD Simulations of the HBV Capsid Complexed with AT130 Reveal Secondary and Tertiary Structural Changes and Mechanisms of Allostery

Viruses ◽

10.3390/v13040564 ◽

2021 ◽

Vol 13 (4) ◽

pp. 564

Author(s):

Carolina Pérez-Segura ◽

Boon Chong Goh ◽

Jodi A. Hadden-Perilla

Keyword(s):

Structural Changes ◽

Core Protein ◽

Salt Bridge ◽

Md Simulations ◽

Health Concern ◽

Genome Packaging ◽

Protein Dimer ◽

B Virus ◽

Correlated Motion ◽

Dynamics Simulations

The hepatitis B virus (HBV) capsid is an attractive drug target, relevant to combating viral hepatitis as a major public health concern. Among small molecules known to interfere with capsid assembly, the phenylpropenamides, including AT130, represent an important antiviral paradigm based on disrupting the timing of genome packaging. Here, all-atom molecular dynamics simulations of an intact AT130-bound HBV capsid reveal that the compound increases spike flexibility and improves recovery of helical secondary structure in the spike tips. Regions of the capsid-incorporated dimer that undergo correlated motion correspond to established sub-domains that pivot around the central chassis. AT130 alters patterns of correlated motion and other essential dynamics. A new conformational state of the dimer is identified, which can lead to dramatic opening of the intradimer interface and disruption of communication within the spike tip. A novel salt bridge is also discovered, which can mediate contact between the spike tip and fulcrum even in closed conformations, revealing a mechanism of direct communication across these sub-domains. Altogether, results describe a dynamical connection between the intra- and interdimer interfaces and enable mapping of allostery traversing the entire core protein dimer.

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Dynamics of the ACE2 - SARS-CoV/SARS-CoV-2 spike protein interface reveal unique mechanisms

10.1101/2020.06.10.143990 ◽

2020 ◽

Author(s):

Amanat Ali ◽

Ranjit Vijayan

Keyword(s):

Salt Bridge ◽

Spike Protein ◽

Health Concern ◽

Treatment Modalities ◽

Receptor Binding Domain ◽

Public Health Concern ◽

Angiotensin Converting Enzyme 2 ◽

Dynamics Simulations ◽

And Function ◽

Host Target

AbstractThe coronavirus disease 2019 (COVID-19) pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a major public health concern. A handful of static structures now provide molecular insights into how SARS-CoV-2 and SARS-CoV interact with its host target, which is the angiotensin converting enzyme 2 (ACE2). Molecular recognition, binding and function are dynamic processes. To evaluate this, multiple all atom molecular dynamics simulations of at least 500 ns each were performed to better understand the structural stability and interfacial interactions between the receptor binding domain of the spike protein of SARS-CoV-2 and SARS-CoV bound to ACE2. Several contacts were observed to form, break and reform in the interface during the simulations. Our results indicate that SARS-CoV and SARS-CoV-2 utilizes unique strategies to achieve stable binding to ACE2. Several differences were observed between the residues of SARS-CoV-2 and SARS-CoV that consistently interacted with ACE2. Notably, a stable salt bridge between Lys417 of SARS-CoV-2 spike protein and Asp30 of ACE2 as well as three stable hydrogen bonds between Tyr449, Gln493, and Gln498 of SARS-CoV-2 and Asp38, Glu35, and Lys353 of ACE2 were observed, which were absent in the SARS-CoV-ACE2 interface. Some previously reported residues, which were suggested to enhance the binding affinity of SARS-CoV-2, were not observed to form stable interactions in these simulations. Stable binding to the host receptor is crucial for virus entry. Therefore, special consideration should be given to these stable interactions while designing potential drugs and treatment modalities to target or disrupt this interface.

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Predicting Methane Diffusivity in Polymeric Membranes by Molecular Dynamics

Advanced Materials Research ◽

10.4028/www.scientific.net/amr.1119.461 ◽

2015 ◽

Vol 1119 ◽

pp. 461-465

Author(s):

M.K. Hadj-Kali ◽

A. Bessadok-Jemai ◽

S. Haider ◽

Y. Alzeghayer

Keyword(s):

Molecular Dynamics ◽

Small Molecules ◽

Diffusion Coefficients ◽

Md Simulations ◽

Polymeric Membranes ◽

Transport Mechanisms ◽

Fluid Equation ◽

Cell Modules ◽

Dynamics Simulations ◽

Materials Studio

Diffusion coefficients of methane (CH4) have been obtained by Molecular Dynamics (MD) simulations combined with Einstein fluid equation. Three polymers were considered, namely polyethylene, polypropylene and poly (cis-1,4-butadiene). All calculations were performed by means of Polymer Builder and Amorphous Cell modules within Materials Studio (Accelrys). The obtained diffusivity results are within the range of published results for similar small molecules. Molecular dynamics simulations proved to be a useful tool for understanding the detailed descriptions and transport mechanisms occurring within the material.

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Variance of Atomic Coordinates as a Dynamical Metric to Distinguish Proteins and Protein-Protein Interactions in Molecular Dynamics Simulations

10.26434/chemrxiv.11684367 ◽

2020 ◽

Author(s):

Sanjoy Paul ◽

Sri Rama Koti Ainavarapu ◽

Ravindra Venkatramani

Keyword(s):

Protein Interactions ◽

Structural Changes ◽

Md Simulations ◽

Comparative Assessment ◽

Protein Protein Interactions ◽

Multiple Protein ◽

Functional Consequences ◽

Global Equilibrium ◽

Dynamics Simulations ◽

Atomic Coordinates

In this manuscript, we introduce the Cumulative Variance of Coordinate Fluctuations (CVCF) along atomistic MD trajectories, as a dynamical metric to examine protein dynamics and sampling convergence in MD simulations. Using model 1D and 2D PES, we first show that CVCF, which traces over the fluctuations of protein atoms as a function of sampling coordinate (time in MD simulations), captures both local and global equilibria to distinguish the underlying PES of proteins. For both model PES and protein trajectories, we compare the information content present in CVCF traces with that obtained using other measures proposed in literature to reveal conditions under which a consistent interpretation of data can be obtained. Importantly, we show that independent of convergence to either local or global equilibrium, the values and features of protein CVCF can provide a comparative assessment of the ruggedness and curvature of the underlying PES sampled by proteins along MD trajectories. Trends in CVCF therefore enable us to compare features of the PES across multiple protein systems using MD simulations. We demonstrate some of the attractive features of a CVCF based analysis on multi-microsecond (ms) MD trajectories of structurally homologous ubiquitin family proteins which present a particularly striking example in nature wherein sequence changes and complexation which do not lead to prominent structural changes bring about dramatic functional consequences.

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In-silico predictive identification of K-RasG12V inhibitors in natural compounds

10.1101/553149 ◽

2019 ◽

Author(s):

Masoud Aliyar ◽

Hassan Aryapour ◽

Majid Mahdavi

Keyword(s):

Small Molecules ◽

Drug Target ◽

Binding Free Energy ◽

Structure Based Drug Design ◽

Ras Protein ◽

Colon Cancers ◽

Reference Ligand ◽

Calculation Results ◽

Poisson Boltzmann ◽

Dynamics Simulations

AbstractAs RAS protein is highly significant in signaling pathways, involving cell growth, differentiation and apoptosis; the Ras GTPase proteins play a significant as a master switch in the appearance of many diseases, including 20-30% of all cancers. So, the K-RasG12V mutant was selected as a drug target in present study. This mutant is involved in gastric cancer, lung and pancreatic carcinoma, and colon cancers. So, we employed the structure-based drug design methods and molecular dynamics simulations to undergo virtual screening on natural products small molecules and predicted some new potent therapeutic inhibitors. Finally, ZINC15671852, ZINC85592862, ZINC85567582 and ZINC03616630 final Hits were identified as potent inhibitors from among more than 79,000 bioactive compounds from natural resource. Molecular Mechanics Poisson-Boltzmann Surface Area (MM-P/GBSA) calculation results have also demonstrated that these molecules obtained higher binding free energy than co-crystalized reference ligand.

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A novel piperazine derivative that targets hepatitis B surface antigen effectively inhibits tenofovir resistant hepatitis B virus

Scientific Reports ◽

10.1038/s41598-021-91196-1 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

S. Kiruthika ◽

Ruchika Bhat ◽

Rozaleen Dash ◽

Anurag S. Rathore ◽

Perumal Vivekanandan ◽

...

Keyword(s):

Hepatitis B Virus ◽

Hepatitis B ◽

Small Molecules ◽

Small Molecule ◽

Surface Antigen ◽

Hepatitis B Surface Antigen ◽

Resonance Spectroscopy ◽

Chronic Hepatitis B Virus ◽

B Virus ◽

Dynamics Simulations

AbstractChronic hepatitis B virus (HBV) infection is a global problem. The loss of hepatitis B surface antigen (HBsAg) in serum is a therapeutic end point. Prolonged therapy with nucleoside/nucleotide analogues targeting the HBV-polymerase may lead to resistance and rarely results in the loss of HBsAg. Therefore, inhibitors targeting HBsAg may have potential therapeutic applications. Here, we used computational virtual screening, docking, and molecular dynamics simulations to identify potential small molecule inhibitors against HBsAg. After screening a million molecules from ZINC database, we identified small molecules with potential anti-HBV activity. Subsequently, cytotoxicity profiles and anti-HBV activities of these small molecules were tested using a widely used cell culture model for HBV. We identified a small molecule (ZINC20451377) which binds to HBsAg with high affinity, with a KD of 65.3 nM, as determined by Surface Plasmon Resonance spectroscopy. Notably, the small molecule inhibited HBsAg production and hepatitis B virion secretion (10 μM) at low micromolar concentrations and was also efficacious against a HBV quadruple mutant (CYEI mutant) resistant to tenofovir. We conclude that this small molecule exhibits strong anti-HBV properties and merits further testing.

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Molecular Dynamics Simulations of Dislocations in TlBr Crystals under an Electrical Field

MRS Advances ◽

10.1557/adv.2016.506 ◽

2016 ◽

Vol 1 (35) ◽

pp. 2459-2464 ◽

Cited By ~ 3

Author(s):

X. W. Zhou ◽

M. E. Foster ◽

P. Yang ◽

F. P. Doty

Keyword(s):

Molecular Dynamics ◽

Structural Changes ◽

Vacancy Concentration ◽

Radiation Detection ◽

Md Simulations ◽

Electrical Field ◽

Electrical Fields ◽

Charge Model ◽

Aging Mechanisms ◽

Dynamics Simulations

ABSTRACTTlBr crystals have superior radiation detection properties; however, their properties degrade in the range of hours to weeks when an operating electrical field is applied. To account for this rapid degradation using the widely-accepted vacancy migration mechanism, the vacancy concentration must be orders of magnitude higher than any conventional estimates. The present work has incorporated a new analytical variable charge model in molecular dynamics (MD) simulations to examine the structural changes of materials under electrical fields. Our simulations indicate that dislocations in TlBr move under electrical fields. This discovery can lead to new understanding of TlBr aging mechanisms under external fields.

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Understanding SARS-CoV-2 budding through molecular dynamics simulations of M and E protein complexes

10.1101/2021.07.26.453874 ◽

2021 ◽

Author(s):

Logan Thrasher Collins ◽

Tamer Elkholy ◽

Shafat Mubin ◽

Ricky Williams ◽

Kayode Ezike ◽

...

Keyword(s):

Molecular Dynamics ◽

Protein Complexes ◽

Md Simulations ◽

Membrane Curvature ◽

M Protein ◽

E Proteins ◽

E Protein ◽

Protein Dimers ◽

Protein Dimer ◽

Dynamics Simulations

SARS-CoV-2 and other coronaviruses pose a major threat to global health, yet treatment efforts have largely ignored the process of envelope assembly, a key part of the coronaviral life cycle. When expressed together, the M and E proteins are sufficient to facilitate coronavirus envelope assembly. Envelope assembly leads to budding of coronavirus particles into the ER-Golgi intermediate compartment (ERGIC) and subsequent maturation of the virus, yet the mechanisms behind the budding process remain poorly understood. Better understanding of budding may enable new types of antiviral therapies. To this end, we ran atomistic molecular dynamics (MD) simulations of SARS-CoV-2 envelope assembly using the Feig laboratory's refined structural models of the M protein dimer and E protein pentamer. Our MD simulations consisted of M protein dimers and E protein pentamers in patches of virtual ERGIC membrane. By examining how these proteins induce membrane curvature in silico, we have obtained insights around how the budding process may occur. In our simulations, M protein dimers acted cooperatively to induce membrane curvature. By contrast, E protein pentamers kept the membrane planar. These results could help guide the development of novel antiviral therapeutics which inhibit coronavirus budding.

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Molecular Modelling of Small Molecule Diffusion in Biopolymer Blends Membranes for Biomedical Applications

Volume 2: Automotive Systems, Bioengineering and Biomedical Technology, Fluids Engineering, Maintenance Engineering and Non-Destructive Evaluation, and Nanotechnology ◽

10.1115/esda2006-95671 ◽

2006 ◽

Author(s):

Mariana Ionita ◽

Davide Silvestri ◽

Alfonso Gautieri ◽

Emiliano Votta ◽

Gianluca Ciardelli ◽

...

Keyword(s):

Small Molecules ◽

Diffusion Coefficients ◽

Diffusion Constant ◽

Polymeric Materials ◽

Md Simulations ◽

Synthetic Polymers ◽

Computational Method ◽

Poly Vinyl Alcohol ◽

Dynamics Simulations ◽

Biological Performance

In order to improve the biological performance of synthetic polymers and to enhance the mechanical characteristics by tailoring the permeability properties of biopolymers, a new class of specifically designed materials (bioartificial polymeric materials), consisting of blends of synthetic polymers and biopolymers, has been recently introduced. In this work we present a computational method based on molecular mechanics (MM) and dynamics (MD) techniques, to investigate their permeability to small molecules. The permeability properties was assessed of poly(vinyl alcohol)-(PVA)- dextran-(Dex) and poly(acrylic acid)-(PAA)-Dex membranes with different blend composition. Amorphous bulk models of PVA–Dex and PAA–Dex mixtures with 80:20, 60:40, 40:60 (w/w) ratios were generated. Two steps have been performed iteratively, the former using a MM simulation for equilibration and the latter using MD simulations for model refinement. Virtual uniaxial traction tests were performed, adopting the Second Derivative (SD) procedure, in order to assess the mechanical behavior of the bulk models. The diffusion coefficients for H2O were determined via NVT molecular dynamics simulations. Using the data of the motion of water inside the bulk models, the diffusivity constant was calculated applying the Einstein equation. Correlation of diffusion coefficients with free volume, was found. The results of the simulations agree with theoretical considerations: as the content of dextran increases from 80:20 to 40:60 a 86 % decrease of the diffusion constant is obtained and the values (range 0.14–56.5 10−6 cm2s−1) have the order of magnitude expected, and similar on the diffusion of small molecules in amorphous polymeric membranes.

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Variance of Atomic Coordinates as a Dynamical Metric to Distinguish Proteins and Protein-Protein Interactions in Molecular Dynamics Simulations

10.26434/chemrxiv.11684367.v1 ◽

2020 ◽

Author(s):

Sanjoy Paul ◽

Sri Rama Koti Ainavarapu ◽

Ravindra Venkatramani

Keyword(s):

Protein Interactions ◽

Structural Changes ◽

Md Simulations ◽

Comparative Assessment ◽

Protein Protein Interactions ◽

Multiple Protein ◽

Functional Consequences ◽

Global Equilibrium ◽

Dynamics Simulations ◽

Atomic Coordinates

In this manuscript, we introduce the Cumulative Variance of Coordinate Fluctuations (CVCF) along atomistic MD trajectories, as a dynamical metric to examine protein dynamics and sampling convergence in MD simulations. Using model 1D and 2D PES, we first show that CVCF, which traces over the fluctuations of protein atoms as a function of sampling coordinate (time in MD simulations), captures both local and global equilibria to distinguish the underlying PES of proteins. For both model PES and protein trajectories, we compare the information content present in CVCF traces with that obtained using other measures proposed in literature to reveal conditions under which a consistent interpretation of data can be obtained. Importantly, we show that independent of convergence to either local or global equilibrium, the values and features of protein CVCF can provide a comparative assessment of the ruggedness and curvature of the underlying PES sampled by proteins along MD trajectories. Trends in CVCF therefore enable us to compare features of the PES across multiple protein systems using MD simulations. We demonstrate some of the attractive features of a CVCF based analysis on multi-microsecond (ms) MD trajectories of structurally homologous ubiquitin family proteins which present a particularly striking example in nature wherein sequence changes and complexation which do not lead to prominent structural changes bring about dramatic functional consequences.

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