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Molecular basis for higher affinity of SARS-CoV-2 spike RBD for human ACE2 receptor.
Delgado, Julián M; Duro, Nalvi; Rogers, David M; Tkatchenko, Alexandre; Pandit, Sagar A; Varma, Sameer.
  • Delgado JM; Department of Cell Biology, Microbiology and Molecular Biology, University of South Florida, Tampa, Florida, USA.
  • Duro N; Department of Cell Biology, Microbiology and Molecular Biology, University of South Florida, Tampa, Florida, USA.
  • Rogers DM; National Center for Computational Sciences, Oak Ridge National Laboratory, Oak Ridge, Tennessee, USA.
  • Tkatchenko A; Department of Physics and Materials Science, University of Luxembourg, Luxembourg, Luxembourg.
  • Pandit SA; Department of Physics, University of South Florida, Tampa, Florida, USA.
  • Varma S; Department of Cell Biology, Microbiology and Molecular Biology, University of South Florida, Tampa, Florida, USA.
Proteins ; 89(9): 1134-1144, 2021 09.
Article in English | MEDLINE | ID: covidwho-1188037
Semantic information from SemMedBD (by NLM)
1. ACE2 gene|ACE2 PART_OF Homo sapiens
Subject
ACE2 gene|ACE2
Predicate
PART_OF
Object
Homo sapiens
2. Basis INTERACTS_WITH ACE2 gene|ACE2
Subject
Basis
Predicate
INTERACTS_WITH
Object
ACE2 gene|ACE2
3. 2019 novel coronavirus CAUSES Infection
Subject
2019 novel coronavirus
Predicate
CAUSES
Object
Infection
4. ACE2 gene|ACE2 PART_OF Homo sapiens
Subject
ACE2 gene|ACE2
Predicate
PART_OF
Object
Homo sapiens
5. Basis INTERACTS_WITH ACE2 gene|ACE2
Subject
Basis
Predicate
INTERACTS_WITH
Object
ACE2 gene|ACE2
6. 2019 novel coronavirus CAUSES Infection
Subject
2019 novel coronavirus
Predicate
CAUSES
Object
Infection
ABSTRACT
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.
Subject(s)
Keywords

Full text: Available Collection: International databases Database: MEDLINE Main subject: Molecular Dynamics Simulation / Spike Glycoprotein, Coronavirus / Angiotensin-Converting Enzyme 2 / SARS-CoV-2 Limits: Humans Language: English Journal: Proteins Journal subject: Biochemistry Year: 2021 Document Type: Article Affiliation country: Prot.26086

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Molecular Dynamics Simulation / Spike Glycoprotein, Coronavirus / Angiotensin-Converting Enzyme 2 / SARS-CoV-2 Limits: Humans Language: English Journal: Proteins Journal subject: Biochemistry Year: 2021 Document Type: Article Affiliation country: Prot.26086