| Objective:To construct the three-dimensional structures of the spike glycoproteins of different mutants of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2).The five energy parameters of each mutants including affinity between spike protein and ACE2,trimers stability,monomers stability,intra-trimer affinity and stability between S1 and S2 subunits were calculated.We study the effect of D614G amino acid substitution mutation on the physicochemical properties of S protein to explore the mechanism of D614G mutation enhancing the infectivity of SARS-CoV-2 and explore the correlation between these five energy parameters and the infectivity of SARS-CoV-2.In order to open up a way to predict the infectivity of SARS-CoV-2 mutant strains through the amino acid sequence of the spike,and provide early warning and advice for public health and epidemic prevention and control.Methods:Firstly,according to the selected 67 mutants,the amino acid sequence of spike was modified,and the three-dimensional structure of spike was modeled by software SwissModel to obtain the three-dimensional structure of spike of each mutant.Then,the protein energy calculation software FoldX was used to calculate the five parameters of the mutant spike.We compared the five parameters of the D614G mutant with the wild type and other mutants,and determined the effect of D614G on the five energy parameters of the spike,so as to explore the mechanism by which the D614G mutation enhances the infectivity of SARS-CoV-2.At the same time,the correlation between the infectivity of SARS-CoV-2 and these five parameters was explored through correlation test and regression analysis.Results:We found that the D614G mutant S protein had stronger trimer stability,inter-trimer affinity,and stability between S1 and S2 subunits compared to the wild-type virus Wuhan-1 and other mutant S proteins.However,the S-ACE2 affinity and monomer stability of D614G mutant were not significantly different from wild-type Wuhan-1 and other mutants.At the same time,it was found that when the D614G mutation occurred at the same time as other site mutations,the effects on the five energy parameters were not linearly additive,and D614G enhanced the trimer stability,the affinity among trimers,and the stability between S1 and S2 of the original mutant S protein.D614G does not affect the S-ACE2 affinity and monomer stability of the original mutant S protein.We found correlations between SARS-CoV-2 mutant pseudovirus infectivity and five parameters.The infectivity of the mutants selected in this paper is positively correlated with the stability of the S protein trimer.For every 1 kcal/mol reduction in trimer folding,the stability of the trimer is enhanced,and the infectivity of the virus is increased by 0.0049 times.The infectivity and the affinity among the trimers also showed a positive correlation.When the binding energy between the trimers decreased by 1 kcal/mol,the affinity between the trimers increased,and the infectivity of the virus increased by 0.027 times.The infectivity was also positively correlated with the stability between the S1 and S2 subunits of the S protein.When the binding energy between the subunits decreased by 1 kcal/mol,the stability between the S1-S2 subunits increased,and the virus infectivity increased by 0.549 times.Since the S-ACE2 affinity and monomer stability of all the mutants selected in this paper have no significant correlation with infectivity,this study cannot determine the relationship between the infectivity of SARS-CoV-2 and these two energy parameters.Conclusion:Effects of D614G mutation on energy parameters of S protein:1)Compared with mutations at other sites,the D614G mutation does not have a significant impact on the S-ACE2 affinity and monomer stability;2)Compared with mutations at other sites,the D614G mutation significantly enhanced the S protein trimer stability,inter-trimer affinity,and S1-S2 subunit stability;3)When D614G mutation and other sites are mutated at the same time,the energy change is not a simple linear addition,and the simultaneous occurrence of D614 mutation will enhance the trimer stability,inter-trimer affinity and S1-S2 subunit stability of original mutant S proteins.Correlation between S protein energy parameters and SARS-CoV-2 infectivity:1)There is no obvious correlation between the infectivity of the mutants selected in this paper,and the S-ACE2 affinity and the monomer stability,so this study cannot determine the correlation between the infectivity and these two energy parameters;2)The infectivity of the mutants selected in this paper is positively correlated with the trimer stability,the inter-trimer affinity and the stability between the S1-S2 subunits of the S protein;3)The S protein trimer stability is highly correlated with the inter-trimer affinity,and the infectivity prediction of SARS-CoV-2 can be performed only by the inter-trimer affinity and the S1-S2 subunit stability. |
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