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Deprecated: Implicit conversion from float 245.2 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Int+J+Infect+Dis 2021 ; 103 (ä): 611-616 Nephropedia Template TP
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Higher binding affinity of furin for SARS-CoV-2 spike (S) protein D614G mutant could be associated with higher SARS-CoV-2 infectivity #MMPMID33075532
Mohammad A; Alshawaf E; Marafie SK; Abu-Farha M; Abubaker J; Al-Mulla F
Int J Infect Dis 2021[Feb]; 103 (ä): 611-616 PMID33075532show ga
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 (DeltaDeltaG = -0.086 kcal mol(-1)). The substitution resulted in stronger binding affinity (K(d) = 1.6 x 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.