Mutations in the B.1.1.7 SARS-CoV-2 Spike Protein Reduce Receptor-Binding Affinity and Induce a Flexible Link to the Fusion Peptide

Socher E, Conrad M, Heger L, Paulsen F, Sticht H, Zunke F, Arnold P (2021)

Publication Language: English

Publication Type: Journal article

Publication year: 2021

Journal

Biomedicines MDPI AG

Book Volume: 9

Journal Issue: 5

URI: https://www.mdpi.com/2227-9059/9/5/525/xml

DOI: 10.3390/biomedicines9050525

Open Access Link: https://www.mdpi.com/2227-9059/9/5/525/xml

Abstract

The B.1.1.7 variant of the SARS-CoV-2 virus shows enhanced infectiousness over the wild type virus, leading to increasing patient numbers in affected areas. Amino acid exchanges within the SARS-CoV-2 spike protein variant of B.1.1.7 affect inter-monomeric contact sites within the trimer (A570D and D614G) as well as the ACE2-receptor interface region (N501Y), which comprises the receptor-binding domain (RBD) of the spike protein. However, the molecular consequences of mutations within B.1.1.7 on spike protein dynamics and stability or ACE2 binding are largely unknown. Here, molecular dynamics simulations comparing SARS-CoV-2 wild type with the B.1.1.7 variant revealed inter-trimeric contact rearrangements, altering the structural flexibility within the spike protein trimer. Furthermore, we found increased flexibility in direct spatial proximity of the fusion peptide due to salt bridge rearrangements induced by the D614G mutation in B.1.1.7. This study also implies a reduced binding affinity for B.1.1.7 with ACE2, as the N501Y mutation restructures the RBD-ACE2 interface, significantly decreasing the linear interaction energy between the RBD and ACE2. Our results demonstrate how mutations found within B.1.1.7 enlarge the flexibility around the fusion peptide and change the RBD-ACE2 interface. We anticipate our findings to be starting points for in depth biochemical and cell biological analyses of B.1.1.7.

Authors with CRIS profile

Eileen Socher Lehrstuhl für Funktionelle und Klinische Anatomie Marcus Conrad Professur für Bioinformatik Lukas Heger Department of Dermatology Friedrich Paulsen Lehrstuhl für Funktionelle und Klinische Anatomie Heinrich Sticht Professur für Bioinformatik Friederike Zunke Juniorprofessur für Translationale Neurowissenschaften Philipp Arnold Lehrstuhl für Funktionelle und Klinische Anatomie

Additional Organisation(s)

Erlangen National High Performance Computing Center (NHR@FAU)

How to cite

APA:

Socher, E., Conrad, M., Heger, L., Paulsen, F., Sticht, H., Zunke, F., & Arnold, P. (2021). Mutations in the B.1.1.7 SARS-CoV-2 Spike Protein Reduce Receptor-Binding Affinity and Induce a Flexible Link to the Fusion Peptide. Biomedicines, 9(5). https://dx.doi.org/10.3390/biomedicines9050525

MLA:

Socher, Eileen, et al. "Mutations in the B.1.1.7 SARS-CoV-2 Spike Protein Reduce Receptor-Binding Affinity and Induce a Flexible Link to the Fusion Peptide." Biomedicines 9.5 (2021).

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