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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Vydáno v:	Proteins, structure, function, and bioinformatics Ročník 90; číslo 5; s. 1044 - 1053
Hlavní autoři:	Williams, Jonathan K., Wang, Baifan, Sam, Andrew, Hoop, Cody L., Case, David A., Baum, Jean
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	Hoboken, USA John Wiley & Sons, Inc 01.05.2022 Wiley Subscription Services, Inc
Témata:	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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Abstract	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.
AbstractList	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. 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.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.
Author	Sam, Andrew Wang, Baifan Case, David A. Baum, Jean Williams, Jonathan K. Hoop, Cody L.
AuthorAffiliation	2 Institute for Quantitative Biomedicine, Rutgers University Piscataway New Jersey USA 1 Department of Chemistry and Chemical Biology Rutgers University Piscataway New Jersey USA
AuthorAffiliation_xml	– name: 1 Department of Chemistry and Chemical Biology Rutgers University Piscataway New Jersey USA – name: 2 Institute for Quantitative Biomedicine, Rutgers University Piscataway New Jersey USA
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Snippet	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... 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...
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SubjectTerms	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
Title	Molecular dynamics analysis of a flexible loop at the binding interface of the SARS‐CoV‐2 spike protein receptor‐binding domain
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