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Higher binding affinity of Furin to SARS-CoV-2 spike (S) protein D614G could be associated with higher SARS-CoV-2 infectivity.
OBJECTIVE: The coronavirus disease-19 (COVID-19) pandemic has caused an exponential rise in death rates and hospitalizations. The aim of this study was to characterize the D614 G mutation of SARS-CoV-2 S-protein, which may affect viral infectivity.
METHODS: The effect of D614 G mutation on the structure and thermodynamic stability of S-protein was analyzed using DynaMut and SCooP. HDOCK and PRODIGY were used to model furin protease binding to the S-protein RARR cleavage site and calculate binding affinities. Molecular dynamic (MD) simulations were used to predict S-protein apo structure, S-protein-furin complex structure, and the free binding energy of the complex.
RESULTS: The D614 G mutation in the G clade of SARS-CoV-2 strains introduced structural mobility and decreased thermal stability of S-protein (ΔΔG: -0.086 kcal/mol). The mutation resulted in a stronger binding affinity (Kd = 1.6 × 10-8) to furin which may enhance S-protein cleavage. Results were corroborated by MD simulations demonstrating higher binding energy of furin to S-protein D614 mutant (-61.9 kcal/mol compared with -56.78 kcal/mol for wild-type S-protein).
CONCLUSIONS: The D614 G mutation in the G clade induced the flexibility of S-protein, resulting in increased furin binding which may enhance S-protein cleave and infiltration of host cells. As such, SARS-CoV-2 D614 G mutation may result in a more virulent strain.
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