scholarly journals Comparison of the binding characteristics of SARS-CoV and SARS-CoV-2 RBDs to ACE2 at different temperatures by MD simulations

2021 ◽  
Author(s):  
Fang-Fang Yan ◽  
Feng Gao
Keyword(s):  
Interaction Mechanism ◽  
Md Simulations ◽  
Angiotensin Converting Enzyme 2 ◽  
Binding Characteristics ◽  
Binding Domains ◽  
Different Temperatures ◽  
Poisson Boltzmann ◽  
Solvated Interaction Energy ◽  
The Difference ◽  
Dynamics Simulations

Abstract Temperature plays a significant role in the survival and transmission of SARS-CoV (severe acute respiratory syndrome coronavirus) and SARS-CoV-2. To reveal the binding differences of SARS-CoV and SARS-CoV-2 receptor-binding domains (RBDs) to angiotensin-converting enzyme 2 (ACE2) at different temperatures at atomic level, 20 molecular dynamics simulations were carried out for SARS-CoV and SARS-CoV-2 RBD–ACE2 complexes at five selected temperatures, i.e. 200, 250, 273, 300 and 350 K. The analyses on structural flexibility and conformational distribution indicated that the structure of the SARS-CoV-2 RBD was more stable than that of the SARS-CoV RBD at all investigated temperatures. Then, molecular mechanics Poisson–Boltzmann surface area and solvated interaction energy approaches were combined to estimate the differences in binding affinity of SARS-CoV and SARS-CoV-2 RBDs to ACE2; it is found that the binding ability of ACE2 to the SARS-CoV-2 RBD was stronger than that to the SARS-CoV RBD at five temperatures, and the main reason for promoting such binding differences is electrostatic and polar interactions between RBDs and ACE2. Finally, the hotspot residues facilitating the binding of SARS-CoV and SARS-CoV-2 RBDs to ACE2, the key differential residues contributing to the difference in binding and the interaction mechanism of differential residues that exist at all investigated temperatures were analyzed and compared in depth. The current work would provide a molecular basis for better understanding of the high infectiousness of SARS-CoV-2 and offer better theoretical guidance for the design of inhibitors targeting infectious diseases caused by SARS-CoV-2.

scholarly journals The β-cyclodextrin/benzene complex and its hydrogen bonds – a theoretical study using molecular dynamics, quantum mechanics and COSMO-RS

2013 ◽  
Vol 9 ◽  
pp. 118-134 ◽  
Author(s):  
Jutta Erika Helga Köhler ◽  
Nicole Grczelschak-Mick
Keyword(s):  
Molecular Dynamics ◽  
Quantum Mechanics ◽  
Hydrogen Bonds ◽  
Md Simulations ◽  
Benzene Molecule ◽  
Glucose Unit ◽  
Hand Orientation ◽  
Different Temperatures ◽  
Dynamics Simulations ◽  
The Right

Four highly ordered hydrogen-bonded models of β-cyclodextrin (β-CD) and its inclusion complex with benzene were investigated by three different theoretical methods: classical quantum mechanics (QM) on AM1 and on the BP/TZVP-DISP3 level of approximation, and thirdly by classical molecular dynamics simulations (MD) at different temperatures (120 K and 273 to 300 K). The hydrogen bonds at the larger O2/O3 rim of empty β-CDs prefer the right-hand orientation, e.g., O3-H…O2-H in the same glucose unit and bifurcated towards …O4 and O3 of the next glucose unit on the right side. On AM1 level the complex energy was −2.75 kcal mol−1 when the benzene molecule was located parallel inside the β-CD cavity and −2.46 kcal mol−1 when it was positioned vertically. The AM1 HOMO/LUMO gap of the empty β-CD with about 12 eV is lowered to about 10 eV in the complex, in agreement with data from the literature. AM1 IR spectra displayed a splitting of the O–H frequencies of cyclodextrin upon complex formation. At the BP/TZVP-DISP3 level the parallel and vertical positions from the starting structures converged to a structure where benzene assumes a more oblique position (−20.16 kcal mol−1 and −20.22 kcal mol−1, resp.) as was reported in the literature. The character of the COSMO-RS σ-surface of β-CD was much more hydrophobic on its O6 rim than on its O2/O3 side when all hydrogen bonds were arranged in a concerted mode. This static QM picture of the β-CD/benzene complex at 0 K was extended by MD simulations. At 120 K benzene was mobile but always stayed inside the cavity of β-CD. The trajectories at 273, 280, 290 and 300 K certainly no longer displayed the highly ordered hydrogen bonds of β-CD and benzene occupied many different positions inside the cavity, before it left the β-CD finally at its O2/O3 side.

A Study of Nanoparticle-Enhanced Heat Transfer

2010 ◽  
Author(s):  
Lawrence M. Jones ◽  
Timothy Sirk ◽  
Eugene Brown
Keyword(s):  
Heat Transfer ◽  
Experimental Data ◽  
Molecular Dynamics ◽  
Heat Flux ◽  
Nuclear Power ◽  
Power Plants ◽  
Md Simulations ◽  
Theoretical Description ◽  
Different Temperatures ◽  
Dynamics Simulations

The study of the heat transfer characteristics of nanofluids, i.e. fluids that are suspensions of nanometer size particles, has gained significant attention in the search for new coolants that can effectively service a variety of needs ranging from the increasing heat transfer demands of ever smaller microelectronic devices to mitigating the effects of loss of coolant accidents in nuclear power plants. Experimental data has shown large increases in thermal conductivity and associated increases in the level of critical heat flux in nuclear reactors; however, in some cases the range of the applicability of the experimental results is uncertain and there is a lack of a theory by which this can be resolved. Complicating the theoretical description of heat transfer in nanofluids is the fact that fluids in the vicinity of the nanoparticles are a complex combination of phase transition, interfacial, and transport phenomena. This paper describes a study in which molecular dynamics simulations were used to enhance the understanding of the effect of nanoparticles on heat transfer. The molecular dynamics (MD) simulations presented here model a Lennard-Jones fluid in a channel where the walls are maintained at different temperatures. The heat flux is calculated for a variety of nanoparticle sizes and concentrations. The results are compared to experimental data in order to provide information that will more confidently bound the data and provide information that will guide the development of more comprehensive theories. We also anticipate that this work could contribute to the design of biosensors where suspended molecules are transported through micro- and nano-channels in the presence of heat transfer.

scholarly journals Computational design of ACE2-based short peptide inhibitors of SARS-CoV-2

2020 ◽  
Author(s):  
Yanxiao Han ◽  
Petr Kral
Keyword(s):  
Molecular Dynamics ◽  
Computational Design ◽  
Peptide Inhibitors ◽  
Converting Enzyme ◽  
Protease Domain ◽  
Alpha Helices ◽  
Angiotensin Converting Enzyme 2 ◽  
Short Peptide ◽  
Binding Domains ◽  
Dynamics Simulations

<div>Peptide inhibitors against the SARS-CoV-2 coronavirus, currently causing a worldwide pandemic, are designed and simulated. The inhibitors are formed by two sequential self-supporting alpha-helices (bundle) extracted from the protease domain (PD) of angiotensin-converting enzyme 2 (ACE2), which binds to the SARS-CoV-2 receptor binding domains. Molecular dynamics simulations revealed that the peptides maintain their secondary structure and provide a highly specific and stable binding (blocking) to SARS-CoV-2, determined by their sequences and conformations. The proposed peptide inhibitors could provide simple therapeutics against the COVID-19 disease.</div>

scholarly journals Adaptive Evolution of Peptide Inhibitors for Mutating SARS-CoV-2

2020 ◽  
Author(s):  
Parth Chaturvedi ◽  
Yanxiao Han ◽  
Petr Kral ◽  
Lela Vukovic
Keyword(s):  
Adaptive Evolution ◽  
Disease Outbreaks ◽  
Global Scale ◽  
Peptide Inhibitors ◽  
Free Energies ◽  
Angiotensin Converting Enzyme 2 ◽  
Binding Domains ◽  
Protein Receptor ◽  
Dynamics Simulations ◽  
Computational Strategy

The SARS-CoV-2 virus is currently causing a worldwide pandemic with dramatic societal consequences for the humankind. In the last decades, disease outbreaks due to such zoonotic pathogens have appeared with an accelerated rate, which calls for an urgent development of<br>adaptive (smart) therapeutics. Here, we develop a computational strategy to adaptively evolve peptides that could selectively inhibit mutating S protein receptor binding domains (RBDs) of different SARS-CoV-2 viral strains from binding to their human host receptor, angiotensin-converting enzyme 2 (ACE2). Starting from suitable peptide templates, based on selected ACE2 segments (natural RBD binder), we gradually modify the templates by random mutations, while retaining those mutations that maximize their RBD-binding free energies. In this adaptive evolution, atomistic molecular dynamics simulations of the template-RBD complexes are iteratively perturbed by the peptide mutations, which are retained under favorable Monte Carlo decisions. The computational search will provide libraries<br>of optimized therapeutics capable of reducing the SARS-CoV-2 infection on a global scale. <br>

Computational optimization of the SARS-CoV-2 receptor-binding-motif affinity for human ACE2

2020 ◽  
Author(s):  
S. Polydorides ◽  
G. Archontis
Keyword(s):  
Angiotensin Converting Enzyme ◽  
Receptor Binding ◽  
Protein Design ◽  
Md Simulations ◽  
Binding Motif ◽  
Converting Enzyme ◽  
Angiotensin Converting Enzyme 2 ◽  
Computational Optimization ◽  
Binding Domains ◽  
Viral Sequences

ABSTRACTThe coronavirus SARS-CoV-2, that is responsible for the COVID-19 pandemic, and the closely related SARS-CoV coronavirus enter cells by binding at the human angiotensin converting enzyme 2 (hACE2). The stronger hACE2 affinity of SARS-CoV-2 has been connected with its higher infectivity. In this work, we study hACE2 complexes with the receptor binding domains (RBDs) of the human SARS-CoV-2 and human SARS-CoV viruses, using all-atom molecular dynamics (MD) simulations and Computational Protein Design (CPD) with a physics-based energy function. The MD simulations identify charge-modifying substitutions between the CoV-2 and CoV RBDs, which either increase or decrease the hACE2 affinity of the SARS-CoV-2 RBD. The combined effect of these mutations is small, and the relative affinity is mainly determined by substitutions at residues in contact with hACE2. Many of these findings are in line and interpret recent experiments. Our CPD calculations redesign positions 455, 493, 494 and 501 of the SARS-CoV-2 RBM, which contact hACE2 in the complex and are important for ACE2 recognition. Sampling is enhanced by an adaptive importance sampling Monte Carlo method. Sequences with increased affinity replace CoV-2 glutamine by a negative residue at position 493, and serine by nonpolar, aromatic or a threonine at position 494. Substitutions at positions positions 455 and 501 have a smaller effect on affinity. Substitutions suggested by our design are seen in viral sequences encountered in other species, including bat and pangolin. Our results might be used to identify potential virus strains with higher human infectivity and assist in the design of peptide-based or peptidomimetic compounds with the potential to inhibit SARS-CoV-2 binding at hACE2.SIGNIFICANCEThe coronavirus SARS-CoV-2 is responsible for the current COVID-19 pandemic. SARS-CoV-2 and the earlier, closely related SARS-CoV virus bind at the human angiotensin converting enzyme 2 (hACE2) receptor at the cell surface. The higher human infectivity of SARS-CoV-2 may be linked to its stronger affinity for hACE2. Here, we study by computational methods complexes of hACE2 with the receptor binding domains (RBDs) of viruses SARS-CoV-2 and SARS-CoV. We identify residues affecting the affinities of the two domains for hACE2. We also propose mutations at key SARS-CoV-2 positions, which might enhance hACE2 affinity. Such mutations may appear in viral strains with increased human infectivity and might assist the design of peptide-based compounds that inhibit infection of human cells by SARS-CoV-2.

scholarly journals Computational drug repurposing study elucidating simultaneous inhibition of entry and replication of novel corona virus by Grazoprevir

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Santosh Kumar Behera ◽  
Nazmina Vhora ◽  
Darshan Contractor ◽  
Amit Shard ◽  
Dinesh Kumar ◽  
...  
Keyword(s):  
Viral Entry ◽  
Clinical Studies ◽  
Drug Repurposing ◽  
Md Simulations ◽  
Angiotensin Converting Enzyme 2 ◽  
Multiple Pathway ◽  
Poisson Boltzmann ◽  
Drug Receptor ◽  
Transmembrane Serine Protease ◽  
Key Residues

AbstractOutcomes of various clinical studies for the coronavirus disease 2019 (COVID-19) treatment indicated that the drug acts via inhibition of multiple pathways (targets) is likely to be more successful and promising. Keeping this hypothesis intact, the present study describes for the first-time, Grazoprevir, an FDA approved anti-viral drug primarily approved for Hepatitis C Virus (HCV), mediated multiple pathway control via synergistic inhibition of viral entry targeting host cell Angiotensin-Converting Enzyme 2 (ACE-2)/transmembrane serine protease 2 (TMPRSS2) and viral replication targeting RNA-dependent RNA polymerase (RdRP). Molecular modeling followed by in-depth structural analysis clearly demonstrated that Grazoprevir interacts with the key residues of these targets. Futher, Molecular Dynamics (MD) simulations showed stability and burial of key residues after the complex formation. Finally, Molecular Mechanics Poisson-Boltzmann Surface Area (MM-PBSA) analysis identified the governing force of drug-receptor interactions and stability. Thus, we believe that Grazoprevir could be an effective therapeutics for the treatment of the COVID-19 pandemic with a promise of unlikely drug resistance owing to multiple inhibitions of eukaryotic and viral proteins, thus warrants further clinical studies.

scholarly journals Computational design of ACE2-based short peptide inhibitors of SARS-CoV-2

2020 ◽  
Author(s):  
Yanxiao Han ◽  
Petr Kral
Keyword(s):  
Molecular Dynamics ◽  
Computational Design ◽  
Peptide Inhibitors ◽  
Converting Enzyme ◽  
Protease Domain ◽  
Alpha Helices ◽  
Angiotensin Converting Enzyme 2 ◽  
Short Peptide ◽  
Binding Domains ◽  
Dynamics Simulations

<div>Peptide inhibitors against the SARS-CoV-2 coronavirus, currently causing a worldwide pandemic, are designed and simulated. The inhibitors are formed by two sequential self-supporting alpha-helices (bundle) extracted from the protease domain (PD) of angiotensin-converting enzyme 2 (ACE2), which binds to the SARS-CoV-2 receptor binding domains. Molecular dynamics simulations revealed that the peptides maintain their secondary structure and provide a highly specific and stable binding (blocking) to SARS-CoV-2, determined by their sequences and conformations. The proposed peptide inhibitors could provide simple therapeutics against the COVID-19 disease.</div>

Adaptive Evolution of Peptide Inhibitors for Mutating SARS-CoV-2

2020 ◽  
Author(s):  
Lela Vukovic ◽  
Yanxiao Han ◽  
Parth Chaturvedi ◽  
Petr Kral
Keyword(s):  
Adaptive Evolution ◽  
Disease Outbreaks ◽  
Global Scale ◽  
Peptide Inhibitors ◽  
Free Energies ◽  
Angiotensin Converting Enzyme 2 ◽  
Binding Domains ◽  
Protein Receptor ◽  
Dynamics Simulations ◽  
Computational Strategy

The SARS-CoV-2 virus is currently causing a worldwide pandemic with dramatic societal consequences for the humankind. In the last decades, disease outbreaks due to such zoonotic pathogens have appeared with an accelerated rate, which calls for an urgent development of<br>adaptive (smart) therapeutics. Here, we develop a computational strategy to adaptively evolve peptides that could selectively inhibit mutating S protein receptor binding domains (RBDs) of different SARS-CoV-2 viral strains from binding to their human host receptor, angiotensin-converting enzyme 2 (ACE2). Starting from suitable peptide templates, based on selected ACE2 segments (natural RBD binder), we gradually modify the templates by random mutations, while retaining those mutations that maximize their RBD-binding free energies. In this adaptive evolution, atomistic molecular dynamics simulations of the template-RBD complexes are iteratively perturbed by the peptide mutations, which are retained under favorable Monte Carlo decisions. The computational search will provide libraries<br>of optimized therapeutics capable of reducing the SARS-CoV-2 infection on a global scale. <br>

Poisson–Boltzmann modeling and molecular dynamics simulations of polyelectrolyte gel diodes in the static regime

Soft Matter ◽  
2020 ◽  
Vol 16 (4) ◽  
pp. 1091-1101
Author(s):  
Vasilii Triandafilidi ◽  
Savvas G. Hatzikiriakos ◽  
Jörg Rottler
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulations ◽  
Md Simulations ◽  
Polyelectrolyte Gel ◽  
Static Regime ◽  
Poisson Boltzmann ◽  
Coupling Strengths ◽  
Dynamics Simulations ◽  
Electrostatic Coupling

We compare MD simulations of a model polyelectrolyte gel diode (PGD) to a Poisson–Boltzmann (PB) model. We study the rectifying behaviour at different electrostatic coupling strengths and suggest an updated PB model for improved modelling of PGDs.

scholarly journals Genetic Variability of Human Angiotensin-Converting Enzyme 2 (hACE2) Among Various Ethnic Populations

2020 ◽  
Author(s):  
Quan Li ◽  
Zanxia Cao ◽  
Proton Rahman
Keyword(s):  
Angiotensin Converting Enzyme ◽  
Missense Mutations ◽  
Converting Enzyme ◽  
East Asians ◽  
Angiotensin Converting Enzyme 2 ◽  
Binding Characteristics ◽  
Functional Studies ◽  
Ethnic Populations ◽  
The Difference

AbstractThere appears to be large regional variations for susceptibility, severity and mortality for Covid-19 infections. We set out to examine genetic differences in the human angiotensin-converting enzyme 2 (hACE2) gene, as its receptor serves as a cellular entry for SARS- CoV-2. By comparing 56,885 Non-Finnish European and 9,197 East Asians (including 1,909 Koreans) four missense mutations were noted in the hACE2 gene. Molecular dynamic demonstrated that two of these variants (K26R and I468V) may affect binding characteristics between S protein of the virus and hACE2 receptor. We also examined hACE2 gene expression in eight global populations from the HapMap3 and noted marginal differences in expression for some populations as compared to the Chinese population. However, for both of our studies, the magnitude of the difference was small and the significance is not clear in the absence of further in vitro and functional studies.

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