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Quantitative analysis of ACE2 binding to coronavirus spike proteins: SARS-CoV-2 vs. SARS-CoV and RaTG13.
Phys Chem Chem Phys. 2021 Jun 30; 23(25):13926-13933.PC

Abstract

The global outbreak of the COVID-19 pandemic is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Bat virus RaTG13 and SARS-CoV are also members of the coronavirus family and SARS-CoV caused a world-wide pandemic in 2003. SARS-CoV-2, SARS-CoV and RaTG13 bind to angiotensin-converting enzyme 2 (ACE2) through their receptor-binding domain (RBD) of the spike protein. SARS-CoV-2 binds ACE2 with a higher binding affinity than SARS-CoV and RaTG13. Here we performed molecular dynamics simulation of these binding complexes and calculated their binding free energies using a computational alanine scanning method. Our MD simulation and hotspot residue analysis showed that the lower binding affinity of SARS-CoV to ACE2 vs. SARS-CoV-2 to ACE2 can be explained by different hotspot interactions in these two systems. We also found that the lower binding affinity of RaTG13 to ACE2 is mainly due to a mutated residue (D501) which resulted in a less favorable complex formation for binding. We also calculated an important mutation of N501Y in SARS-CoV-2 using both alanine scanning calculation and a thermodynamic integration (TI) method. Both calculations confirmed a significant increase of the binding affinity of the N501Y mutant to ACE2 and explained its molecular mechanism. The present work provides an important theoretical basis for understanding the molecular mechanism in coronavirus spike protein binding to human ACE2.

Authors+Show Affiliations

Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, Shanghai Key Laboratory of Green Chemistry & Chemical Process, School of Chemistry and Molecular Engineering, East China Normal University at Shanghai, 200062, China. john.zhang@nyu.edu.Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, Shanghai Key Laboratory of Green Chemistry & Chemical Process, School of Chemistry and Molecular Engineering, East China Normal University at Shanghai, 200062, China. john.zhang@nyu.edu and NYU-ECNU Center for Computational Chemistry at NYU Shanghai, Shanghai 200062, China and Department of Chemistry, New York University, NY NY 10003, USA and Collaborative Innovation Center of Extreme Optics, Shanxi University, Taiyuan, Shanxi 030006, China.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

34137759

Citation

Li, Zhendong, and John Z H. Zhang. "Quantitative Analysis of ACE2 Binding to Coronavirus Spike Proteins: SARS-CoV-2 Vs. SARS-CoV and RaTG13." Physical Chemistry Chemical Physics : PCCP, vol. 23, no. 25, 2021, pp. 13926-13933.
Li Z, Zhang JZH. Quantitative analysis of ACE2 binding to coronavirus spike proteins: SARS-CoV-2 vs. SARS-CoV and RaTG13. Phys Chem Chem Phys. 2021;23(25):13926-13933.
Li, Z., & Zhang, J. Z. H. (2021). Quantitative analysis of ACE2 binding to coronavirus spike proteins: SARS-CoV-2 vs. SARS-CoV and RaTG13. Physical Chemistry Chemical Physics : PCCP, 23(25), 13926-13933. https://doi.org/10.1039/d1cp01075a
Li Z, Zhang JZH. Quantitative Analysis of ACE2 Binding to Coronavirus Spike Proteins: SARS-CoV-2 Vs. SARS-CoV and RaTG13. Phys Chem Chem Phys. 2021 Jun 30;23(25):13926-13933. PubMed PMID: 34137759.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Quantitative analysis of ACE2 binding to coronavirus spike proteins: SARS-CoV-2 vs. SARS-CoV and RaTG13. AU - Li,Zhendong, AU - Zhang,John Z H, PY - 2021/6/18/pubmed PY - 2021/7/8/medline PY - 2021/6/17/entrez SP - 13926 EP - 13933 JF - Physical chemistry chemical physics : PCCP JO - Phys Chem Chem Phys VL - 23 IS - 25 N2 - The global outbreak of the COVID-19 pandemic is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Bat virus RaTG13 and SARS-CoV are also members of the coronavirus family and SARS-CoV caused a world-wide pandemic in 2003. SARS-CoV-2, SARS-CoV and RaTG13 bind to angiotensin-converting enzyme 2 (ACE2) through their receptor-binding domain (RBD) of the spike protein. SARS-CoV-2 binds ACE2 with a higher binding affinity than SARS-CoV and RaTG13. Here we performed molecular dynamics simulation of these binding complexes and calculated their binding free energies using a computational alanine scanning method. Our MD simulation and hotspot residue analysis showed that the lower binding affinity of SARS-CoV to ACE2 vs. SARS-CoV-2 to ACE2 can be explained by different hotspot interactions in these two systems. We also found that the lower binding affinity of RaTG13 to ACE2 is mainly due to a mutated residue (D501) which resulted in a less favorable complex formation for binding. We also calculated an important mutation of N501Y in SARS-CoV-2 using both alanine scanning calculation and a thermodynamic integration (TI) method. Both calculations confirmed a significant increase of the binding affinity of the N501Y mutant to ACE2 and explained its molecular mechanism. The present work provides an important theoretical basis for understanding the molecular mechanism in coronavirus spike protein binding to human ACE2. SN - 1463-9084 UR - https://www.unboundmedicine.com/medline/citation/34137759/Quantitative_analysis_of_ACE2_binding_to_coronavirus_spike_proteins:_SARS_CoV_2_vs__SARS_CoV_and_RaTG13_ DB - PRIME DP - Unbound Medicine ER -