scholarly journals Binding mechanism of SARS-CoV-2 spike protein with human ACE2 receptor

2020 ◽  
Author(s):  
Rajendra P Koirala ◽  
Bidhya Thapa ◽  
Shyam P Khanal ◽  
Jhulan Powrel ◽  
Rajendra P Adhikari ◽  
...  
Keyword(s):  
Free Energy ◽  
Contact Surface ◽  
Hydrophobic Interactions ◽  
Binding Free Energy ◽  
Umbrella Sampling ◽  
Spike Protein ◽  
Receptor Protein ◽  
Virus Protein ◽  
Binding Mechanism ◽  
Binding Interface

Abstract SARS-CoV-2 virus interacts via C-terminal domain of spike protein to human cell receptor protein hACE2. Amino acid residues residing at the interface play vital role in binding of SARS-CoV-2 CTD to hACE2. The detailed atomic level inves- tigation of interactions at binding interface of SARS-CoV-2 CTD/hACE2 provides indispensable information on better understanding of location for drug target. In the present work, we have studied the dynamical behaviour of the complex by ana- lyzing the molecular dynamics (MD) trajectories. The major interacting residues of SARS-CoV-2 CTD and hACE2 have been identified by analyzing the non-bonded interactions such as hydrogen bondings, salt bridges, hydrophobic interactions, van der Waals interactions etc. Umbrella sampling method has been used to estimate the binding free energy for in-depth understanding of binding mechanism between virus protein and host receptor. The binding free energy difference, key residues at the interface, important atomic interactions and contact surface areas have been compared with the molecular complex of SARS-CoV and hACE2. Relatively larger contact surface area, more non-bonded interactions as well as greater binding free energy provide the evidence for favorable binding of SARS-CoV-2 with hACE2 receptor than SARS-CoV.

Compared with SARS-CoV2 wild type's spike protein, the SARS-CoV2 omicron's receptor binding motif has adopted a more SARS-CoV1 and/or bat/civet-like structure.

2021 ◽  
Author(s):  
Michael O. Glocker ◽  
Kwabena F. M. Opuni ◽  
Hans-Juergen Thiesen
Keyword(s):  
Free Energy ◽  
Receptor Binding ◽  
Free Energy Calculations ◽  
Viral Fitness ◽  
Spike Protein ◽  
Receptor Protein ◽  
Binding Motif ◽  
Energy Calculations ◽  
Selection Processes ◽  
Protein Receptor

Our study focuses on free energy calculations of SARS-Cov2 spike protein receptor binding motives (RBMs) from wild type and variants-of-concern with particular emphasis on currently emerging SARS- CoV2 omicron variants of concern (VOC). Our computational free energy analysis underlines the occurrence of positive selection processes that specify omicron host adaption and bring changes on the molecular level into context with clinically relevant observations. Our free energy calculations studies regarding the interaction of omicron's RBM with human ACE2 shows weaker binding to ACE2 than alpha's, delta's, or wild type's RBM. Thus, less virus is predicted to be generated in time per infected cell. Our mutant analyses predict with focus on omicron variants a reduced spike-protein binding to ACE2--receptor protein possibly enhancing viral fitness / transmissibility and resulting in a delayed induction of danger signals as trade-off. Finally, more virus is produced but less per cell accompanied with delayed Covid-19 immunogenicity and pathogenicity. Regarding the latter, more virus is assumed to be required to initiate inflammatory immune responses.

scholarly journals Omicron SARS-CoV-2 Variant Spike Protein Shows an Increased Affinity to the Human ACE2 Receptor: An In Silico Analysis

Pathogens ◽  
2021 ◽  
Vol 11 (1) ◽  
pp. 45
Author(s):  
Joseph Thomas Ortega ◽  
Beata Jastrzebska ◽  
Hector Rafael Rangel
Keyword(s):  
Free Energy ◽  
Electrostatic Interactions ◽  
Structural Model ◽  
Binding Free Energy ◽  
In Silico Analysis ◽  
Spike Protein ◽  
Medical Community ◽  
Converting Enzyme ◽  
Angiotensin Converting Enzyme 2 ◽  
Silico Analysis

The rise of SARS-CoV-2 variants, with changes that could be related to an increased virus pathogenicity, have received the interest of the scientific and medical community. In this study, we evaluated the changes that occurred in the viral spike of the SARS-CoV-2 Omicron variant and whether these changes modulate the interactions with the angiotensin-converting enzyme 2 (ACE2) host receptor. The mutations associated with the Omicron variant were retrieved from the GISAID and covariants.org databases, and a structural model was built using the SWISS-Model server. The interaction between the spike and the human ACE2 was evaluated using two different docking software, Zdock and Haddock. We found that the binding free energy was lower for the Omicron variant as compared to the WT spike. In addition, the Omicron spike protein showed an increased number of electrostatic interactions with ACE2 than the WT spike, especially the interactions related to charged residues. This study contributes to a better understanding of the changes in the interaction between the Omicron spike and the human host ACE2 receptor.

scholarly journals Possibility of HIV-1 Protease Inhibitors-Clinical Trial Drugs as Repurposed Drugs for SARSCoV-2 Main Protease: A Molecular Docking, Molecular Dynamics and Binding Free Energy Simulation Study

2020 ◽  
Author(s):  
Ancy Iruthayaraj ◽  
Sivanandam Magudeeswaran ◽  
Kumaradhas Poomani
Keyword(s):  
Clinical Trial ◽  
Amino Acids ◽  
Free Energy ◽  
Binding Free Energy ◽  
Drug Repurposing ◽  
Md Simulations ◽  
Binding Mechanism ◽  
Main Protease ◽  
Repurposed Drugs ◽  
Hiv 1

<p>Initially, the SARS-CoV-2 virus was emerged from Wuhan, China and rapidly spreading across the world and urges the scientific community to develop antiviral therapeutic agents. Among several strategies, drug repurposing will help to react immediately to overcome COVID-19 pandemic. In the present study, we have chosen two clinical trial drugs TMB607 and TMC310911 are the inhibitors of HIV-1 protease to use as the inhibitors of SARS-CoV-2 main protease (M<sup>pro</sup>) enzyme. To make use of these two inhibitors as the repurposed drugs for COVID-19, it is essential to know the molecular basis of binding mechanism of these two molecules with the SARS-CoV-2 main protease (M<sup>pro</sup>). Understand the binding mechanism; we performed the molecular docking, molecular dynamics (MD) simulations and binding free energy calculations against the SARS-CoV-2 M<sup>pro</sup>. The docking results indicate that both molecules form intermolecular interactions with the active site amino acids of M<sup>pro</sup> enzyme. However, during the MD simulations, TMB607 forms strong interactions with the key amino acids of M<sup>pro</sup> and remains intact. The RMSD and RMSF values of both complexes were stable throughout the MD simulations. The MM-GBSA binding free energy values of both complexes are -43.7 and -34.9 kcal/mol, respectively. This <i>in silico</i> study proves that the TMB607 molecule binds strongly with the SARS-CoV-2 M<sup>pro</sup> enzyme and it is suitable for the drug repurposing of COVID-19 and further drug designing.</p>

scholarly journals Comparison of the umbrella sampling and the double decoupling method in binding free energy predictions for SAMPL6 octa-acid host–guest challenges

2018 ◽  
Vol 32 (10) ◽  
pp. 1075-1086 ◽  
Author(s):  
Naohiro Nishikawa ◽  
Kyungreem Han ◽  
Xiongwu Wu ◽  
Florentina Tofoleanu ◽  
Bernard R. Brooks
Keyword(s):  
Free Energy ◽  
Binding Free Energy ◽  
Umbrella Sampling ◽  
Decoupling Method ◽  
Octa Acid

scholarly journals Structure-Based Virtual Screening and Molecular Dynamic Simulation Studies to Identify Novel Cytochrome bc1 Inhibitors as Antimalarial Agents

2013 ◽  
Vol 2013 ◽  
pp. 1-9 ◽  
Author(s):  
Rahul P. Gangwal ◽  
Gaurao V. Dhoke ◽  
Mangesh V. Damre ◽  
Kanchan Khandelwal ◽  
Abhay T. Sangamwar
Keyword(s):  
Free Energy ◽  
Molecular Docking ◽  
Molecular Dynamic Simulation ◽  
Molecular Dynamic ◽  
Dynamic Simulation ◽  
Hydrophobic Interactions ◽  
Binding Free Energy ◽  
Van Der Waals Interactions ◽  
Electrostatic Energy ◽  
Hydrogen Bond Acceptor

Cytochrome bc1 (EC 1.10.2.2, bc1) is an essential component of the cellular respiratory chain, which catalyzes electron transfer from quinol to cytochrome c and concomitantly the translocation of protons across the membrane. It has been identified as a promising target in malaria parasites. The structure-based pharmacophore modelling and molecular dynamic simulation approach have been employed to identify novel inhibitors of cytochrome bc1. The best structure-based pharmacophore hypothesis (Hypo1) consists of one hydrogen bond acceptor (HBA), one general hydrophobic (HY), and two hydrophobic aromatic features (HYAr). Further, hydrogen interactions and hydrophobic interactions of known potent inhibitors with cytochrome bc1 were compared with Hypo1, which showed that the Hypo1 has good predictive ability. The validated Hypo1 was used to screen the chemical databases. The hits obtained were subsequently subjected to the molecular docking analysis to identify false-positive hits. Moreover, the molecular docking results were further validated by molecular dynamics simulations. Binding-free energy analysis using MM-GBSA method reveals that the van der Waals interactions and the electrostatic energy provide the basis for favorable absolute free energy of the complex. The five virtual hits were identified as possible candidates for the designing of potent cytochrome bc1 inhibitors.

scholarly journals Understanding the microscopic binding mechanism of hydroxylated and sulfated polybrominated diphenyl ethers with transthyretin by molecular docking, molecular dynamics simulations and binding free energy calculations

2017 ◽  
Vol 13 (4) ◽  
pp. 736-749 ◽  
Author(s):  
Huiming Cao ◽  
Yuzhen Sun ◽  
Ling Wang ◽  
Chunyan Zhao ◽  
Jianjie Fu ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Free Energy ◽  
Molecular Docking ◽  
Polybrominated Diphenyl Ethers ◽  
Binding Free Energy ◽  
Free Energy Calculations ◽  
Binding Mechanism ◽  
Diphenyl Ethers ◽  
Binding Free Energy Calculations ◽  
Dynamics Simulations

The binding of TTR with sulfated-PBDEs and OH-PBDEs shows different molecular recognition mechanisms.

scholarly journals A replica exchange umbrella sampling (REUS) approach to predict host–guest binding free energies in SAMPL8 challenge

2021 ◽  
Author(s):  
Mahdi Ghorbani ◽  
Phillip S. Hudson ◽  
Michael R. Jones ◽  
Félix Aviat ◽  
Rubén Meana-Pañeda ◽  
...  
Keyword(s):  
Free Energy ◽  
Binding Free Energy ◽  
Umbrella Sampling ◽  
Free Energy Calculations ◽  
Replica Exchange ◽  
Free Energies ◽  
Guest Binding ◽  
Binding Free Energy Calculations ◽  
Force Field Parameters ◽  
Binding Free Energies

AbstractIn this study, we report binding free energy calculations of various drugs-of-abuse to Cucurbit-[8]-uril as part of the SAMPL8 blind challenge. Force-field parameters were obtained from force-matching with different quantum mechanical levels of theory. The Replica Exchange Umbrella Sampling (REUS) approach was used with a cylindrical restraint to enhance the sampling of host–guest binding. Binding free energy was calculated by pulling the guest molecule from one side of the symmetric and cylindrical host, then into and through the host, and out the other side (bidirectional) as compared to pulling only to the bound pose inside the cylindrical host (unidirectional). The initial results with force-matched MP2 parameter set led to RMSE of 4.68 $${\text{kcal}}/{\text{mol}}$$ kcal / mol from experimental values. However, the follow-up study with CHARMM generalized force field parameters and force-matched PM6-D3H4 parameters resulted in RMSEs from experiment of $$2.65$$ 2.65 and $$1.72 {\text{kcal}}/{\text{mol}}$$ 1.72 kcal / mol , respectively, which demonstrates the potential of REUS for accurate binding free energy calculation given a more suitable description of energetics. Moreover, we compared the free energies for the so called bidirectional and unidirectional free energy approach and found that the binding free energies were highly similar. However, one issue in the bidirectional approach is the asymmetry of profile on the two sides of the host. This is mainly due to the insufficient sampling for these larger systems and can be avoided by longer sampling simulations. Overall REUS shows great promise for binding free energy calculations.

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