Molecular basis for higher affinity of SARS-CoV-2 spike RBD for human ACE2 receptor.
COVID-19
SARS-CoV
SARS-CoV-2
allostery
molecular dynamics
protein dynamics
protein-protein interactions
viral entry
Journal
Proteins
ISSN: 1097-0134
Titre abrégé: Proteins
Pays: United States
ID NLM: 8700181
Informations de publication
Date de publication:
09 2021
09 2021
Historique:
revised:
31
03
2021
received:
19
02
2021
accepted:
02
04
2021
pubmed:
18
4
2021
medline:
10
8
2021
entrez:
17
4
2021
Statut:
ppublish
Résumé
Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has caused substantially more infections, deaths, and economic disruptions than the 2002-2003 SARS-CoV. The key to understanding SARS-CoV-2's higher infectivity lies partly in its host receptor recognition mechanism. Experiments show that the human angiotensin converting enzyme 2 (ACE2) protein, which serves as the primary receptor for both CoVs, binds to the receptor binding domain (RBD) of CoV-2's spike protein stronger than SARS-CoV's spike RBD. The molecular basis for this difference in binding affinity, however, remains unexplained from X-ray structures. To go beyond insights gained from X-ray structures and investigate the role of thermal fluctuations in structure, we employ all-atom molecular dynamics simulations. Microseconds-long simulations reveal that while CoV and CoV-2 spike-ACE2 interfaces have similar conformational binding modes, CoV-2 spike interacts with ACE2 via a larger combinatorics of polar contacts, and on average, makes 45% more polar contacts. Correlation analysis and thermodynamic calculations indicate that these differences in the density and dynamics of polar contacts arise from differences in spatial arrangements of interfacial residues, and dynamical coupling between interfacial and non-interfacial residues. These results recommend that ongoing efforts to design spike-ACE2 peptide blockers will benefit from incorporating dynamical information as well as allosteric coupling effects.
Identifiants
pubmed: 33864655
doi: 10.1002/prot.26086
pmc: PMC8250905
doi:
Substances chimiques
Receptors, Virus
0
Spike Glycoprotein, Coronavirus
0
spike protein, SARS-CoV-2
0
ACE2 protein, human
EC 3.4.17.23
Angiotensin-Converting Enzyme 2
EC 3.4.17.23
Types de publication
Journal Article
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
1134-1144Subventions
Organisme : Office of Science of the U.S. Department of Energy
ID : DE-AC05-00OR22725
Informations de copyright
© 2021 Wiley Periodicals LLC.
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