Molecular dynamics analysis of a flexible loop at the binding interface of the SARS‐CoV‐2 spike protein receptor‐binding domain

Since the identification of the SARS‐CoV‐2 virus as the causative agent of the current COVID‐19 pandemic, considerable effort has been spent characterizing the interaction between the Spike protein receptor‐binding domain (RBD) and the human angiotensin converting enzyme 2 (ACE2) receptor. This has...

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Vydané v:	Proteins, structure, function, and bioinformatics Ročník 90; číslo 5; s. 1044 - 1053
Hlavní autori:	Williams, Jonathan K., Wang, Baifan, Sam, Andrew, Hoop, Cody L., Case, David A., Baum, Jean
Médium:	Journal Article
Jazyk:	English
Vydavateľské údaje:	Hoboken, USA John Wiley & Sons, Inc 01.05.2022 Wiley Subscription Services, Inc
Predmet:	ACE2 Angiotensin Angiotensin-Converting Enzyme 2 Binding Binding Sites coronavirus COVID-19 Crystal structure Flexibility Humans Molecular dynamics Molecular Dynamics Simulation Mutation Pandemics Peptidyl-dipeptidase A Protein Binding protein conformation protein dynamics protein modeling Protein structure Proteins Receptors SARS-CoV-2 Severe acute respiratory syndrome Severe acute respiratory syndrome coronavirus 2 Special issue: SARS‐CoV‐2 special issue for Proteins spike glycoprotein Spike Glycoprotein, Coronavirus - chemistry Spike protein Viral diseases SARS-CoV-2 spike glycoprotein molecular dynamics simulation protein dynamics coronavirus protein conformation protein modeling
ISSN:	0887-3585, 1097-0134, 1097-0134
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Shrnutí:	Since the identification of the SARS‐CoV‐2 virus as the causative agent of the current COVID‐19 pandemic, considerable effort has been spent characterizing the interaction between the Spike protein receptor‐binding domain (RBD) and the human angiotensin converting enzyme 2 (ACE2) receptor. This has provided a detailed picture of the end point structure of the RBD‐ACE2 binding event, but what remains to be elucidated is the conformation and dynamics of the RBD prior to its interaction with ACE2. In this work, we utilize molecular dynamics simulations to probe the flexibility and conformational ensemble of the unbound state of the receptor‐binding domain from SARS‐CoV‐2 and SARS‐CoV. We have found that the unbound RBD has a localized region of dynamic flexibility in Loop 3 and that mutations identified during the COVID‐19 pandemic in Loop 3 do not affect this flexibility. We use a loop‐modeling protocol to generate and simulate novel conformations of the CoV2‐RBD Loop 3 region that sample conformational space beyond the ACE2 bound crystal structure. This has allowed for the identification of interesting substates of the unbound RBD that are lower energy than the ACE2‐bound conformation, and that block key residues along the ACE2 binding interface. These novel unbound substates may represent new targets for therapeutic design.
Bibliografia:	Funding information Rutgers University Center for COVID‐19 Response and Pandemic Preparedness, Grant/Award Number: CCRP2; National Institutes of Health Grant, Grant/Award Number: GM136431 ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 Funding information Rutgers University Center for COVID‐19 Response and Pandemic Preparedness, Grant/Award Number: CCRP2; National Institutes of Health Grant, Grant/Award Number: GM136431
ISSN:	0887-3585 1097-0134 1097-0134
DOI:	10.1002/prot.26208