Conformational Variability Correlation Prediction of Transmissibility and Neutralization Escape Ability for Multiple Mutation SARS-CoV-2 Strains using SSSCPreds.

Hiroshi Izumi,Laurence A. Nafie,Rina K. Dukor

doi:10.1021/acsomega.1c03055

Hiroshi Izumi, Laurence A. Nafie + Show 1 more

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https://doi.org/10.1021/acsomega.1c03055

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Abstract

Identifying the fundamental cause of transmissibility of multiple mutation strains and vaccine nullification is difficult in general and is a source of significant concern. The conformational variability of the mutation sites for B.1.617.2 (Δ), B.1.617.1 (κ), B.1.427/429 (ε), P.1 (γ), B.1.351 (β), B.1.1.7 (α), S477N, and the wild-type strain has been assessed using a deep neural-network-based prediction program of conformational flexibility or rigidity in proteins (SSSCPreds). We find that although the conformation of G614 is rigid, which is assigned as a left-handed (LH) α-helix-type one, that of D614 is flexible without the hydrogen bonding latch to T859. The rigidity of glycine, which stabilizes the local conformation more effectively than that of aspartic acid with the latch, thereby contributes to the reduction of S1 shedding, high expression, and increase in infectivity. The finding that the sequence flexibility/rigidity map pattern of B.1.1.7 is similar to that of the wild-type strain but is largely different from those of B.1.351 and P.1 correlates with the minor escape ability of B.1.1.7. The increased rigidity of the amino acid sequence YRYRLFR from the SSSCPreds data of B.1.427/429 near the L452R mutation site contributes to the 2-fold increased B.1.427/B.1.429 viral shedding in vivo and the increase in transmissibility relative to wild-type circulating strains in a similar manner to D614G. The concordance and rigidity ratios of multiple mutation strains such as B.1.617.2 against the wild-type one at the receptor-binding domain (RBD) and receptor-binding motif (RBM) regions provide a good indication of the transmissibility and neutralization escape ability except for binding affinity of mutation sites such as N501Y.

Highlights

Multiple mutation SARS-CoV-2 strains such as B.1.427/429 (ε)[1] and P.1 (γ)[2] have been newly registered as variants of concern by the Centers for Disease Control and Prevention (CDC)
Conformational variability of the mutation site is one of the factors that deeply relate to the infection of SARS-CoV-2.3,8 Recently, we reported a deep neural-network-based prediction program of conformational flexibility or rigidity in proteins (SSSCPreds)[8] using supersecondary structure code (SSSC).[9−11] The sequence flexibility/rigidity map of SARSCoV-2 receptor-binding domain (RBD), obtained from SSSCPreds, resembles the sequence-to-phenotype maps of ACE2-binding affinity and expression, which were experimentally obtained by the deep mutational scanning.[3]
We report that the conformational variability assessment using SSSCPreds rationalizes well the transmissibility and the neutralization escape ability of SARSCoV-2 strains

Summary

Introduction

Multiple mutation SARS-CoV-2 strains such as B.1.427/429 (ε)[1] and P.1 (γ)[2] have been newly registered as variants of concern by the Centers for Disease Control and Prevention (CDC). In January 2021, novel strains B.1.427/429, which contain S13I, W152C, L452R, and D614G mutations in the spike protein, were found in California (Figure 1A).[1] The change of transmissibility was largely ascribed to the mutations in receptor-binding domain (RBD). B.1.427/429 exhibited an 18.6−24% increase in transmissibility relative to wild-type circulating strains,[1] a quantitative deep mutational scanning of L452R indicated the constant binding affinity against the wild-type one in contrast with the high expression.[3] B.1.617, which is classified as a variant of interest by CDC is prevalent in India.[4] Most recently, B.1.617.2 (Δ) has been classified as a variant of concern. The main protein substitutions are L452R, E484Q (or T478K), D614G, and P681R

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