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...

Full description

Saved in:
Bibliographic Details
Published in:Proteins, structure, function, and bioinformatics Vol. 90; no. 5; pp. 1044 - 1053
Main Authors: Williams, Jonathan K., Wang, Baifan, Sam, Andrew, Hoop, Cody L., Case, David A., Baum, Jean
Format: Journal Article
Language:English
Published: Hoboken, USA John Wiley & Sons, Inc 01.05.2022
Wiley Subscription Services, Inc
Subjects:
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
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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.
Bibliography: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