Higher binding affinity of furin for SARS-CoV-2 spike (S) protein D614G mutant could be associated with higher SARS-CoV-2 infectivity.

ABSTRACT:

Objective

The coronavirus disease 2019 (COVID-19) pandemic has caused an exponential rise in death rates and hospitalizations. The aim of this study was to characterize the D614G substitution in the severe acute respiratory syndome coronavirus 2 (SARS-CoV-2) spike glycoprotein (S protein), which may affect viral infectivity.

Methods

The effect of D614G substitution on the structure and thermodynamic stability of the S protein was analyzed with use of DynaMut and SCooP. HDOCK and PRODIGY were used to model furin protease binding to the S protein RRAR cleavage site and calculate binding affinities. Molecular dynamics simulations were used to predict the S protein apo structure, the S protein-furin complex structure, and the free binding energy of the complex.

Results

The D614G substitution in the G clade of SARS-CoV-2 strains introduced structural mobility and decreased the thermal stability of the S protein (??G?=?-0.086?kcal mol^-1). The substitution resulted in stronger binding affinity (K_d?=?1.6?×?10^-8) for furin, which may enhance S protein cleavage. The results were corroborated by molecular dynamics simulations demonstrating higher binding energy of furin and the S protein D614G mutant (-61.9?kcal?mol^-1 compared with -56.78?kcal?mol^-1 for wild-type S protein).

Conclusions

The D614G substitution in the G clade induced flexibility of the S protein, resulting in increased furin binding, which may enhance S protein cleavage and infiltration of host cells. Therefore, the SARS-CoV-2 D614G substitution may result in a more virulent strain.

SUBMITTER: Mohammad A 

PROVIDER: S-EPMC7567667 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature