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.

Eileen Socher,Friederike Zunke,Lukas Heger,Heinrich Sticht,Philipp Arnold,Marcus Conrad,Friedrich Paulsen

doi:10.3390/biomedicines9050525

Eileen Socher, Friederike Zunke + Show 5 more

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https://doi.org/10.3390/biomedicines9050525

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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.

Highlights

IntroductionThe outbreak of the severe acute respiratory syndrome (SARS) caused by the SARSlike coronavirus SARS-CoV-2 has become a global pandemic with daily increasing numbers of infections, and deaths exceeding 2.5 million world-wide [1]
To compare flexibility between the severe acute respiratory syndrome (SARS)-CoV-2 wild type and B.1.1.7 variant, root-mean-square fluctuation (RMSF) values were calculated for the backbone atoms of all individual residues over 200 ns simulation time
Highest RMSF values were calculated for the receptor-binding domain (RBD) with flexibility of up to 10 Å, especially at the interface positions where interaction with angiotensin-converting enzyme 2 (ACE2) would occur upon receptor binding (Figure S2a–c)

Summary

Introduction

The outbreak of the severe acute respiratory syndrome (SARS) caused by the SARSlike coronavirus SARS-CoV-2 has become a global pandemic with daily increasing numbers of infections, and deaths exceeding 2.5 million world-wide [1]. On top of the rapid, global spread of SARS-CoV-2, new and more contagious virus variants comprise an additional threat [2,3,4,5]. The novel SARS-CoV-2 variant B.1.1.7 first emerged in southeast England in November 2020 and is estimated to be 56% more transmissible [6]. This variant is characterized by several amino acid deletions and exchanges, with most of the protein-coding muta-

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