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Dynamics of the ACE2-SARS-CoV-2/SARS-CoV spike protein interface reveal unique mechanisms.
Sci Rep. 2020 08 26; 10(1):14214.SR

Abstract

The 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 500 ns or 1 μs all-atom molecular dynamics simulations were performed to better understand the structural stability and interfacial interactions between the receptor binding domain of the spike (S) 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-2 and SARS-CoV 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 S 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 ACE2-SARS-CoV 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. Molecular mechanics-generalized Born surface area based free energy of binding was observed to be higher for SARS-CoV-2 in all 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.

Authors+Show Affiliations

Department of Biology, College of Science, United Arab Emirates University, PO Box 15551, Al Ain, United Arab Emirates.Department of Biology, College of Science, United Arab Emirates University, PO Box 15551, Al Ain, United Arab Emirates. ranjit.v@uaeu.ac.ae.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

32848162

Citation

Ali, Amanat, and Ranjit Vijayan. "Dynamics of the ACE2-SARS-CoV-2/SARS-CoV Spike Protein Interface Reveal Unique Mechanisms." Scientific Reports, vol. 10, no. 1, 2020, p. 14214.
Ali A, Vijayan R. Dynamics of the ACE2-SARS-CoV-2/SARS-CoV spike protein interface reveal unique mechanisms. Sci Rep. 2020;10(1):14214.
Ali, A., & Vijayan, R. (2020). Dynamics of the ACE2-SARS-CoV-2/SARS-CoV spike protein interface reveal unique mechanisms. Scientific Reports, 10(1), 14214. https://doi.org/10.1038/s41598-020-71188-3
Ali A, Vijayan R. Dynamics of the ACE2-SARS-CoV-2/SARS-CoV Spike Protein Interface Reveal Unique Mechanisms. Sci Rep. 2020 08 26;10(1):14214. PubMed PMID: 32848162.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Dynamics of the ACE2-SARS-CoV-2/SARS-CoV spike protein interface reveal unique mechanisms. AU - Ali,Amanat, AU - Vijayan,Ranjit, Y1 - 2020/08/26/ PY - 2020/06/04/received PY - 2020/08/12/accepted PY - 2020/8/28/entrez PY - 2020/8/28/pubmed PY - 2020/9/15/medline SP - 14214 EP - 14214 JF - Scientific reports JO - Sci Rep VL - 10 IS - 1 N2 - The 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 500 ns or 1 μs all-atom molecular dynamics simulations were performed to better understand the structural stability and interfacial interactions between the receptor binding domain of the spike (S) 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-2 and SARS-CoV 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 S 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 ACE2-SARS-CoV 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. Molecular mechanics-generalized Born surface area based free energy of binding was observed to be higher for SARS-CoV-2 in all 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. SN - 2045-2322 UR - https://www.unboundmedicine.com/medline/citation/32848162/Dynamics_of_the_ACE2_SARS_CoV_2/SARS_CoV_spike_protein_interface_reveal_unique_mechanisms_ L2 - http://dx.doi.org/10.1038/s41598-020-71188-3 DB - PRIME DP - Unbound Medicine ER -