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Binding mode of SARS-CoV-2 fusion peptide to human cellular membrane.
Gorgun, Defne; Lihan, Muyun; Kapoor, Karan; Tajkhorshid, Emad.
  • Gorgun D; Theoretical and Computational Biophysics Group, NIH Center for Macromolecular Modeling and Bioinformatics, Beckman Institute for Advanced Science and Technology, Department of Biochemistry, and Center for Biophysics and Quantitative Biology, University of Illinois at Urbana-Champaign, Urbana, Illino
  • Lihan M; Theoretical and Computational Biophysics Group, NIH Center for Macromolecular Modeling and Bioinformatics, Beckman Institute for Advanced Science and Technology, Department of Biochemistry, and Center for Biophysics and Quantitative Biology, University of Illinois at Urbana-Champaign, Urbana, Illino
  • Kapoor K; Theoretical and Computational Biophysics Group, NIH Center for Macromolecular Modeling and Bioinformatics, Beckman Institute for Advanced Science and Technology, Department of Biochemistry, and Center for Biophysics and Quantitative Biology, University of Illinois at Urbana-Champaign, Urbana, Illino
  • Tajkhorshid E; Theoretical and Computational Biophysics Group, NIH Center for Macromolecular Modeling and Bioinformatics, Beckman Institute for Advanced Science and Technology, Department of Biochemistry, and Center for Biophysics and Quantitative Biology, University of Illinois at Urbana-Champaign, Urbana, Illino
Biophys J ; 120(14): 2914-2926, 2021 07 20.
Article in English | MEDLINE | ID: covidwho-1605082
Preprint
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Semantic information from SemMedBD (by NLM)
1. Plasma membrane PART_OF Homo sapiens
Subject
Plasma membrane
Predicate
PART_OF
Object
Homo sapiens
2. Peptides COEXISTS_WITH M Protei
Subject
Peptides
Predicate
COEXISTS_WITH
Object
M Protei
3. Plasma membrane PART_OF Mammals
Subject
Plasma membrane
Predicate
PART_OF
Object
Mammals
4. FES wt Allele|FDPS|FES PART_OF Helice
Subject
FES wt Allele|FDPS|FES
Predicate
PART_OF
Object
Helice
5. Peptides AFFECTS Membrane
Subject
Peptides
Predicate
AFFECTS
Object
Membrane
6. Plasma membrane PART_OF Homo sapiens
Subject
Plasma membrane
Predicate
PART_OF
Object
Homo sapiens
7. Peptides COEXISTS_WITH M Protein, multiple myeloma
Subject
Peptides
Predicate
COEXISTS_WITH
Object
M Protein, multiple myeloma
8. Plasma membrane PART_OF Mammals
Subject
Plasma membrane
Predicate
PART_OF
Object
Mammals
9. FES wt Allele|FDPS|FES PART_OF Helice
Subject
FES wt Allele|FDPS|FES
Predicate
PART_OF
Object
Helice
10. Peptides AFFECTS Membrane
Subject
Peptides
Predicate
AFFECTS
Object
Membrane
ABSTRACT
Infection of human cells by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) relies on its binding to a specific receptor and subsequent fusion of the viral and host cell membranes. The fusion peptide (FP), a short peptide segment in the spike protein, plays a central role in the initial penetration of the virus into the host cell membrane, followed by the fusion of the two membranes. Here, we use an array of molecular dynamics simulations that take advantage of the highly mobile membrane mimetic model to investigate the interaction of the SARS-CoV2 FP with a lipid bilayer representing mammalian cellular membranes at an atomic level and to characterize the membrane-bound form of the peptide. Six independent systems were generated by changing the initial positioning and orientation of the FP with respect to the membrane, and each system was simulated in five independent replicas, each for 300 ns. In 73% of the simulations, the FP reaches a stable, membrane-bound configuration, in which the peptide deeply penetrated into the membrane. Clustering of the results reveals three major membrane-binding modes (binding modes 1-3), in which binding mode 1 populates over half of the data points. Taking into account the sequence conservation among the viral FPs and the results of mutagenesis studies establishing the role of specific residues in the helical portion of the FP in membrane association, the significant depth of penetration of the whole peptide, and the dense population of the respective cluster, we propose that the most deeply inserted membrane-bound form (binding mode 1) represents more closely the biologically relevant form. Analysis of FP-lipid interactions shows the involvement of specific residues, previously described as the "fusion-active core residues," in membrane binding. Taken together, the results shed light on a key step involved in SARS-CoV2 infection, with potential implications in designing novel inhibitors.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: SARS-CoV-2 / COVID-19 Limits: Animals / Humans Language: English Journal: Biophys J Year: 2021 Document Type: Article

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Full text: Available Collection: International databases Database: MEDLINE Main subject: SARS-CoV-2 / COVID-19 Limits: Animals / Humans Language: English Journal: Biophys J Year: 2021 Document Type: Article