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An Active Site Inhibitor Induces Conformational Penalties for ACE2 Recognition by the Spike Protein of SARS-CoV-2.
J Phys Chem B. 2021 03 18; 125(10):2533-2550.JP

Abstract

The novel RNA virus, severe acute respiratory syndrome coronavirus II (SARS-CoV-2), is currently the leading cause of mortality in 2020, having led to over 1.6 million deaths and infecting over 75 million people worldwide by December 2020. While vaccination has started and several clinical trials for a number of vaccines are currently underway, there is a pressing need for a cure for those already infected with the virus. Of particular interest in the design of anti-SARS-CoV-2 therapeutics is the human protein angiotensin converting enzyme II (ACE2) to which this virus adheres before entry into the host cell. The SARS-CoV-2 virion binds to cell-surface bound ACE2 via interactions of the spike protein (s-protein) on the viral surface with ACE2. In this paper, we use all-atom molecular dynamics simulations and binding enthalpy calculations to determine the effect that a bound ACE2 active site inhibitor (MLN-4760) would have on the binding affinity of SARS-CoV-2 s-protein with ACE2. Our analysis indicates that the binding enthalpy could be reduced for s-protein adherence to the active site inhibitor-bound ACE2 protein by as much as 1.48-fold as an upper limit. This weakening of binding strength was observed to be due to the destabilization of the interactions between ACE2 residues Glu-35, Glu-37, Tyr-83, Lys-353, and Arg-393 and the SARS-CoV-2 s-protein receptor binding domain (RBD). The conformational changes were shown to lead to weakening of ACE2 interactions with SARS-CoV-2 s-protein, therefore reducing s-protein binding strength. Further, we observed increased conformational lability of the N-terminal helix and a conformational shift of a significant portion of the ACE2 motifs involved in s-protein binding, which may affect the kinetics of the s-protein binding when the small molecule inhibitor is bound to the ACE2 active site. These observations suggest potential new ways for interfering with the SARS-CoV-2 adhesion by modulating ACE2 conformation through distal active site inhibitor binding.

Authors+Show Affiliations

School of Engineering, RMIT University, Melbourne, Victoria 3001, Australia.School of Engineering, RMIT University, Melbourne, Victoria 3001, Australia.Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria 3800, Australia.Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria 3800, Australia.School of Engineering, RMIT University, Melbourne, Victoria 3001, Australia.

Pub Type(s)

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

Language

eng

PubMed ID

33657325

Citation

Williams-Noonan, Billy J., et al. "An Active Site Inhibitor Induces Conformational Penalties for ACE2 Recognition By the Spike Protein of SARS-CoV-2." The Journal of Physical Chemistry. B, vol. 125, no. 10, 2021, pp. 2533-2550.
Williams-Noonan BJ, Todorova N, Kulkarni K, et al. An Active Site Inhibitor Induces Conformational Penalties for ACE2 Recognition by the Spike Protein of SARS-CoV-2. J Phys Chem B. 2021;125(10):2533-2550.
Williams-Noonan, B. J., Todorova, N., Kulkarni, K., Aguilar, M. I., & Yarovsky, I. (2021). An Active Site Inhibitor Induces Conformational Penalties for ACE2 Recognition by the Spike Protein of SARS-CoV-2. The Journal of Physical Chemistry. B, 125(10), 2533-2550. https://doi.org/10.1021/acs.jpcb.0c11321
Williams-Noonan BJ, et al. An Active Site Inhibitor Induces Conformational Penalties for ACE2 Recognition By the Spike Protein of SARS-CoV-2. J Phys Chem B. 2021 03 18;125(10):2533-2550. PubMed PMID: 33657325.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - An Active Site Inhibitor Induces Conformational Penalties for ACE2 Recognition by the Spike Protein of SARS-CoV-2. AU - Williams-Noonan,Billy J, AU - Todorova,Nevena, AU - Kulkarni,Ketav, AU - Aguilar,Marie-Isabel, AU - Yarovsky,Irene, Y1 - 2021/03/03/ PY - 2021/3/4/pubmed PY - 2021/3/26/medline PY - 2021/3/3/entrez SP - 2533 EP - 2550 JF - The journal of physical chemistry. B JO - J Phys Chem B VL - 125 IS - 10 N2 - The novel RNA virus, severe acute respiratory syndrome coronavirus II (SARS-CoV-2), is currently the leading cause of mortality in 2020, having led to over 1.6 million deaths and infecting over 75 million people worldwide by December 2020. While vaccination has started and several clinical trials for a number of vaccines are currently underway, there is a pressing need for a cure for those already infected with the virus. Of particular interest in the design of anti-SARS-CoV-2 therapeutics is the human protein angiotensin converting enzyme II (ACE2) to which this virus adheres before entry into the host cell. The SARS-CoV-2 virion binds to cell-surface bound ACE2 via interactions of the spike protein (s-protein) on the viral surface with ACE2. In this paper, we use all-atom molecular dynamics simulations and binding enthalpy calculations to determine the effect that a bound ACE2 active site inhibitor (MLN-4760) would have on the binding affinity of SARS-CoV-2 s-protein with ACE2. Our analysis indicates that the binding enthalpy could be reduced for s-protein adherence to the active site inhibitor-bound ACE2 protein by as much as 1.48-fold as an upper limit. This weakening of binding strength was observed to be due to the destabilization of the interactions between ACE2 residues Glu-35, Glu-37, Tyr-83, Lys-353, and Arg-393 and the SARS-CoV-2 s-protein receptor binding domain (RBD). The conformational changes were shown to lead to weakening of ACE2 interactions with SARS-CoV-2 s-protein, therefore reducing s-protein binding strength. Further, we observed increased conformational lability of the N-terminal helix and a conformational shift of a significant portion of the ACE2 motifs involved in s-protein binding, which may affect the kinetics of the s-protein binding when the small molecule inhibitor is bound to the ACE2 active site. These observations suggest potential new ways for interfering with the SARS-CoV-2 adhesion by modulating ACE2 conformation through distal active site inhibitor binding. SN - 1520-5207 UR - https://www.unboundmedicine.com/medline/citation/33657325/An_Active_Site_Inhibitor_Induces_Conformational_Penalties_for_ACE2_Recognition_by_the_Spike_Protein_of_SARS_CoV_2_ L2 - https://doi.org/10.1021/acs.jpcb.0c11321 DB - PRIME DP - Unbound Medicine ER -