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Article

Coevolution, Dynamics and Allostery Conspire in Shaping Cooperative Binding and Signal Transmission of the SARS-CoV-2 Spike Protein with Human Angiotensin-Converting Enzyme 2

1
Graduate Program in Computational and Data Sciences, Schmid College of Science and Technology, Chapman University, Orange, CA 92866, USA
2
Department of Biomedical and Pharmaceutical Sciences, Chapman University School of Pharmacy, Irvine, CA 92618, USA
Int. J. Mol. Sci. 2020, 21(21), 8268; https://doi.org/10.3390/ijms21218268
Received: 18 October 2020 / Revised: 2 November 2020 / Accepted: 3 November 2020 / Published: 4 November 2020
(This article belongs to the Collection Feature Papers in Molecular Biophysics)
Binding to the host receptor is a critical initial step for the coronavirus SARS-CoV-2 spike protein to enter into target cells and trigger virus transmission. A detailed dynamic and energetic view of the binding mechanisms underlying virus entry is not fully understood and the consensus around the molecular origins behind binding preferences of SARS-CoV-2 for binding with the angiotensin-converting enzyme 2 (ACE2) host receptor is yet to be established. In this work, we performed a comprehensive computational investigation in which sequence analysis and modeling of coevolutionary networks are combined with atomistic molecular simulations and comparative binding free energy analysis of the SARS-CoV and SARS-CoV-2 spike protein receptor binding domains with the ACE2 host receptor. Different from other computational studies, we systematically examine the molecular and energetic determinants of the binding mechanisms between SARS-CoV-2 and ACE2 proteins through the lens of coevolution, conformational dynamics, and allosteric interactions that conspire to drive binding interactions and signal transmission. Conformational dynamics analysis revealed the important differences in mobility of the binding interfaces for the SARS-CoV-2 spike protein that are not confined to several binding hotspots, but instead are broadly distributed across many interface residues. Through coevolutionary network analysis and dynamics-based alanine scanning, we established linkages between the binding energy hotspots and potential regulators and carriers of signal communication in the virus–host receptor complexes. The results of this study detailed a binding mechanism in which the energetics of the SARS-CoV-2 association with ACE2 may be determined by cumulative changes of a number of residues distributed across the entire binding interface. The central findings of this study are consistent with structural and biochemical data and highlight drug discovery challenges of inhibiting large and adaptive protein–protein interfaces responsible for virus entry and infection transmission. View Full-Text
Keywords: SARS-CoV spike protein; ACE2; coevolution; molecular dynamics; alanine scanning; binding free energy; allosteric interactions; signal transmission SARS-CoV spike protein; ACE2; coevolution; molecular dynamics; alanine scanning; binding free energy; allosteric interactions; signal transmission
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MDPI and ACS Style

Verkhivker, G. Coevolution, Dynamics and Allostery Conspire in Shaping Cooperative Binding and Signal Transmission of the SARS-CoV-2 Spike Protein with Human Angiotensin-Converting Enzyme 2. Int. J. Mol. Sci. 2020, 21, 8268. https://doi.org/10.3390/ijms21218268

AMA Style

Verkhivker G. Coevolution, Dynamics and Allostery Conspire in Shaping Cooperative Binding and Signal Transmission of the SARS-CoV-2 Spike Protein with Human Angiotensin-Converting Enzyme 2. International Journal of Molecular Sciences. 2020; 21(21):8268. https://doi.org/10.3390/ijms21218268

Chicago/Turabian Style

Verkhivker, Gennady. 2020. "Coevolution, Dynamics and Allostery Conspire in Shaping Cooperative Binding and Signal Transmission of the SARS-CoV-2 Spike Protein with Human Angiotensin-Converting Enzyme 2" International Journal of Molecular Sciences 21, no. 21: 8268. https://doi.org/10.3390/ijms21218268

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