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Key Interacting Residues between RBD of SARS-CoV-2 and ACE2 Receptor: Combination of Molecular Dynamics Simulation and Density Functional Calculation.
Jawad, Bahaa; Adhikari, Puja; Podgornik, Rudolf; Ching, Wai-Yim.
  • Jawad B; Department of Physics and Astronomy, University of Missouri-Kansas City, Kansas City, Missouri 64110, United States.
  • Adhikari P; Department of Physics and Astronomy, University of Missouri-Kansas City, Kansas City, Missouri 64110, United States.
  • Podgornik R; Wenzhou Institute of the University of Chinese Academy of Sciences, Wenzhou, Zhejiang 325000, China.
  • Ching WY; School of Physical Sciences and Kavli Institute of Theoretical Science, University of Chinese Academy of Sciences, Beijing 100049, China.
J Chem Inf Model ; 61(9): 4425-4441, 2021 09 27.
Article in English | MEDLINE | ID: covidwho-1371584
ABSTRACT
The spike protein of SARS-CoV-2 binds to the ACE2 receptor via its receptor-binding domain (RBD), with the RBD-ACE2 complex presenting an essential molecular target for vaccine development to stall the virus infection proliferation. The computational analyses at molecular, amino acid (AA), and atomic levels have been performed systematically to identify the key interacting AAs in the formation of the RBD-ACE2 complex for SARS-CoV and SARS-CoV-2 with its Alpha and Beta variants. Our study uses the molecular dynamics (MD) simulations with the molecular mechanics generalized Born surface area (MM-GBSA) method to predict the binding free energy (BFE) and to determine the actual interacting AAs, as well as two ab initio quantum chemical protocols based on the density functional theory (DFT) implementation. Based on MD results, Q493, Y505, Q498, N501, T500, N487, Y449, F486, K417, Y489, F456, Y495, and L455 have been identified as hotspots in SARS-CoV-2 RBD, while those in ACE2 are K353, K31, D30, D355, H34, D38, Q24, T27, Y83, Y41, and E35. RBD with Alpha and Beta variants has slightly different interacting AAs due to N501Y mutation. Both the electrostatic and hydrophobic interactions are the main driving force to form the AA-AA binding pairs. We confirm that Q493, Q498, N501, F486, K417, and F456 in RBD are the key residues responsible for the tight binding of SARS-CoV-2 with ACE2 compared to SARS-CoV. RBD with the Alpha variant binds with ACE2 stronger than the wild-type RBD or Beta. In the Beta variant, K417N reduces the binding, E484K slightly enhances it, and N501Y significantly increases it as in Alpha. The DFT results reveal that N487, Q493, Y449, T500, G496, G446, and G502 in RBD of SARS2 form pairs via specific hydrogen bonding with Q24, H34, E35, D38, Y41, Q42, and K353 in ACE2.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: Molecular Dynamics Simulation / COVID-19 Type of study: Prognostic study Topics: Vaccines / Variants Limits: Humans Language: English Journal: J Chem Inf Model Journal subject: Medical Informatics / Chemistry Year: 2021 Document Type: Article Affiliation country: Acs.jcim.1c00560

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Molecular Dynamics Simulation / COVID-19 Type of study: Prognostic study Topics: Vaccines / Variants Limits: Humans Language: English Journal: J Chem Inf Model Journal subject: Medical Informatics / Chemistry Year: 2021 Document Type: Article Affiliation country: Acs.jcim.1c00560