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Computational decomposition reveals reshaping of the SARS-CoV-2-ACE2 interface among viral variants expressing the N501Y mutation.
J Cell Biochem. 2021 12; 122(12):1863-1872.JC

Abstract

Variants of concern of the SARS-CoV-2 virus with an asparagine-to-tyrosine substitution at position 501 (N501Y) in the receptor-binding domain (RBD) show enhanced infectivity compared to wild-type, resulting in an altered pandemic situation in affected areas. These SARS-Cov-2 variants comprise the two Alpha variants (B.1.1.7, United Kingdom and B.1.1.7 with the additional E484K mutation), the Beta variant (B.1.351, South Africa), and the Gamma variant (P.1, Brazil). Understanding the binding modalities between these viral variants and the host cell receptor ACE2 allows to depict changes, but also common motifs of virus-host cell interaction. The trimeric spike protein expressed at the viral surface contains the RBD that forms the molecular interface with ACE2. All the above-mentioned variants carry between one and three amino acid exchanges within the interface-forming region of the RBD, thereby altering the binding interface with ACE2. Using molecular dynamics (MD) simulations and decomposition of intermolecular contacts between the RBD and ACE2, we identified phenylalanine 486, glutamine 498, threonine 500, and tyrosine 505 as important interface-forming residues across viral variants. However, especially the N501Y exchange increased contact formation for this residue and also induced some local conformational changes. Comparing here, the in silico generated B.1.1.7 RBD-ACE2 complex with the now available experimentally solved structure reveals very similar behavior during MD simulation. We demonstrate, how computational methods can help to identify differences in conformation as well as contact formation for newly emerging viral variants. Altogether, we provide extensive data on all N501Y expressing SARS-CoV-2 variants of concern with respect to their interaction with ACE2 and how this induces reshaping of the RBD-ACE2 interface.

Authors+Show Affiliations

Functional and Clinical Anatomy, Institute of Anatomy, Friedrich-Alexander University Erlangen-Nürnberg (FAU), Erlangen, Germany. Institute for Clinical and Molecular Virology, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nürnberg (FAU), Erlangen, Germany.Division of Bioinformatics, Institute of Biochemistry, Friedrich-Alexander University Erlangen-Nürnberg (FAU), Erlangen, Germany.Department of Dermatology, Laboratory of Dendritic Cell Biology, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nürnberg (FAU), Erlangen, Germany.Functional and Clinical Anatomy, Institute of Anatomy, Friedrich-Alexander University Erlangen-Nürnberg (FAU), Erlangen, Germany. Department of Operative Surgery and Topographic Anatomy, Sechenov University, Moscow, Russia.Division of Bioinformatics, Institute of Biochemistry, Friedrich-Alexander University Erlangen-Nürnberg (FAU), Erlangen, Germany. Erlangen National High Performance Computing Center (NHR@FAU), Friedrich-Alexander University Erlangen-Nürnberg (FAU), Erlangen, Germany.Department of Molecular Neurology, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nürnberg (FAU), Erlangen, Germany.Functional and Clinical Anatomy, Institute of Anatomy, Friedrich-Alexander University Erlangen-Nürnberg (FAU), Erlangen, Germany.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

34516024

Citation

Socher, Eileen, et al. "Computational Decomposition Reveals Reshaping of the SARS-CoV-2-ACE2 Interface Among Viral Variants Expressing the N501Y Mutation." Journal of Cellular Biochemistry, vol. 122, no. 12, 2021, pp. 1863-1872.
Socher E, Conrad M, Heger L, et al. Computational decomposition reveals reshaping of the SARS-CoV-2-ACE2 interface among viral variants expressing the N501Y mutation. J Cell Biochem. 2021;122(12):1863-1872.
Socher, E., Conrad, M., Heger, L., Paulsen, F., Sticht, H., Zunke, F., & Arnold, P. (2021). Computational decomposition reveals reshaping of the SARS-CoV-2-ACE2 interface among viral variants expressing the N501Y mutation. Journal of Cellular Biochemistry, 122(12), 1863-1872. https://doi.org/10.1002/jcb.30142
Socher E, et al. Computational Decomposition Reveals Reshaping of the SARS-CoV-2-ACE2 Interface Among Viral Variants Expressing the N501Y Mutation. J Cell Biochem. 2021;122(12):1863-1872. PubMed PMID: 34516024.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Computational decomposition reveals reshaping of the SARS-CoV-2-ACE2 interface among viral variants expressing the N501Y mutation. AU - Socher,Eileen, AU - Conrad,Marcus, AU - Heger,Lukas, AU - Paulsen,Friedrich, AU - Sticht,Heinrich, AU - Zunke,Friederike, AU - Arnold,Philipp, Y1 - 2021/09/13/ PY - 2021/08/05/received PY - 2021/08/16/accepted PY - 2021/9/14/pubmed PY - 2021/12/21/medline PY - 2021/9/13/entrez KW - COVID-19 KW - SARS-CoV-2 KW - angiotensin-converting enzyme 2 (ACE2) KW - coronavirus KW - molecular dynamics simulations KW - spike protein SP - 1863 EP - 1872 JF - Journal of cellular biochemistry JO - J Cell Biochem VL - 122 IS - 12 N2 - Variants of concern of the SARS-CoV-2 virus with an asparagine-to-tyrosine substitution at position 501 (N501Y) in the receptor-binding domain (RBD) show enhanced infectivity compared to wild-type, resulting in an altered pandemic situation in affected areas. These SARS-Cov-2 variants comprise the two Alpha variants (B.1.1.7, United Kingdom and B.1.1.7 with the additional E484K mutation), the Beta variant (B.1.351, South Africa), and the Gamma variant (P.1, Brazil). Understanding the binding modalities between these viral variants and the host cell receptor ACE2 allows to depict changes, but also common motifs of virus-host cell interaction. The trimeric spike protein expressed at the viral surface contains the RBD that forms the molecular interface with ACE2. All the above-mentioned variants carry between one and three amino acid exchanges within the interface-forming region of the RBD, thereby altering the binding interface with ACE2. Using molecular dynamics (MD) simulations and decomposition of intermolecular contacts between the RBD and ACE2, we identified phenylalanine 486, glutamine 498, threonine 500, and tyrosine 505 as important interface-forming residues across viral variants. However, especially the N501Y exchange increased contact formation for this residue and also induced some local conformational changes. Comparing here, the in silico generated B.1.1.7 RBD-ACE2 complex with the now available experimentally solved structure reveals very similar behavior during MD simulation. We demonstrate, how computational methods can help to identify differences in conformation as well as contact formation for newly emerging viral variants. Altogether, we provide extensive data on all N501Y expressing SARS-CoV-2 variants of concern with respect to their interaction with ACE2 and how this induces reshaping of the RBD-ACE2 interface. SN - 1097-4644 UR - https://www.unboundmedicine.com/medline/citation/34516024/Computational_decomposition_reveals_reshaping_of_the_SARS_CoV_2_ACE2_interface_among_viral_variants_expressing_the_N501Y_mutation_ DB - PRIME DP - Unbound Medicine ER -