Study Of Fusion Peptide Release For Spike Protein Of SARS-CoV-2

With the spread of the COVID-19 virus,research on its characteristics is constantly progressing.The spike protein of the COVID-19 virus is known to be able to recognize host cell receptors and initiate membrane fusion.The host recognition mechanism for the protein has been thoroughly studied and well understood.However,the membrane fusion mechanism of the spike protein is still uncertain and further research is needed.To investigate the membrane fusion mechanism of the COVID-19 virus spike protein,this study used various modifications including removal of the S1 subunit and cleavage at the S2’ site,to modify the spike protein in 56 different ways,and used a structure-based allatom model(SMOG model)to describe protein structure and force field.Molecular dynamics(MD)simulations and analyses were performed using the GROMACS software.In addition,targeting the COVID-19 main protease(Mpro),a potential drug library from Enamine was screened using molecular docking and MD simulations.A potential drug precursor was identified.The main computational simulation results are as follows:(1)When the S1 subunit of chain A,B,or C is removed,and at the same time,the S2’site of the spike protein S2 subunit of chain B,C,or A is cleaved,the fusion peptide in the corresponding S2 subunit of the spike protein may be released.Our simulation results suggest that the conditions for releasing the fusion peptide may be lower than previously expected(removal of all 3 S1 subunits and cleavage of all 3 S2’ sites).(2)Using MOE software,a potential drug library of small molecules(a total of 1200 small molecules)targeting the COVID-19 main protease(Mpro)provided by Enamine was screened and subjected to 50 ns of Amber MD simulation.Then,the binding strength of the small molecule with Mpro was verified through RMSD,RMSF,MMPBSA,and interaction analysis.The study found that the compound Z56795247 in Enamine’s potential COVID-19 main protease inhibitor database may be a potential Mpro inhibitor,with low free energy of binding to Mpro.(3)A script was designed based on the Python language to assist the SMOG2 software package in handling nonlinear glycan chemical bond lists,which can be used to generate sugar molecules and identify the chemical bonds between sugar molecules and residues.This script provides a convenient tool to list the chemical bonds formed between glycan molecules,which improves the efficiency of the SMOG MD simulation preparation relatedIn this work,the possible release conditions of the fusion peptide of the COVID-19 spike protein were studied for the first time,as described in(1),and the mechanism of fusion peptide release was explored,providing theoretical information for related experimental research.