Molecular Dynamics Study On The Binding Property Of SARS-CoV-2 Spike Protein To Receptor And Its Application In Drug Design

Coronavirus disease 2019(COVID-19)is a severe respiratory disease caused by the severe acute respiratory syndrome coronavirus 2(SARS-CoV-2).Due to the strong infectivity and high latency of pathogens,COVID-19 has developed into a severe epidemic within a few months.The prevalence of COVID-19 not only affects the daily lives of individuals,but also has a significant impact on the global economy and public health.Thus,ensuring rapid,safe and effective development of drugs and vaccines has always been an urgent problem.This thesis first proposed a systematic vaccine and drug development strategy using the widely studied bacteria as an example.This strategy mainly includes three parts: target discovery,target analysis and molecular dynamics analysis.Target discovery plays an important role in the treatment of infectious diseases and epidemics.Researchers are working on the discovery of drug and vaccine targets through multiple methods,including the analyses of comparative subtractive genome,core genome,replication-related proteins,transcriptomics and riboswitches.On the basis of in-depth analysis of the target,the structure of target proteins,drugs and epitopes can be predicted.In addition,molecular dynamics analysis of drug/epitope-target protein complexes is an important standard for testing the suitability of these screened drugs and vaccines.This systematic strategy not only aids in the design of vaccines and drugs against bacteria,but also in the design of drugs and vaccines to treat COVID-19.Secondly,the binding properties of the spike(S)protein of SARS-CoV-2 and severe acute respiratory syndrome coronavirus(SARS-CoV)to host receptor ACE2 were compared at different temperatures.Repeated molecular dynamics simulations were carried out for SARS-CoV and SARS-CoV-2 RBD-ACE2 complexes at five selected temperatures,i.e.200 K,250 K,273 K,300 K and 350 K.The analyses on structural flexibility and conformational distribution indicated that the structure of SARS-CoV-2 RBD was more stable than that of SARS-CoV RBD at all investigated temperatures.Then,molecular mechanics Poisson-Boltzmann surface area(MM-PBSA)and solvated interaction energy(SIE)approaches were used to estimate the differences in binding affinity of SARS-CoV and SARS-CoV-2 RBDs to ACE2;it is found that the binding ability of SARS-CoV-2 RBD to ACE2 was stronger than of SARS-CoV RBD at five temperatures,and the main reason for promoting such binding differences is electrostatic and polar interactions between RBD and ACE2.Finally,the binding mechanism of SARS-CoV and SARS-CoV-2 RBDs to ACE2 was also deeply analyzed.Next,the binding properties of the spike protein from SARS-CoV-2 variant of concern(VOC)to receptor or antibodies were compared.By the beginning of 2022,five SARS-CoV-2 variants of concern have emerged,i.e.alpha strain(B.1.1.7),beta strain(B.1.351),gamma strain(P.1),delta strain(B.1.617.2)and omicron strain(B.1.1.529).These mutant strains show different degrees of transmission ability and immune escape ability,which bring great difficulties to clinical treatment.To explore the differences in the binding mechanism of different variants to host receptor and their differences in immune escape ability,this work conducted a preliminary exploration of different variants through computational methods.Preliminary conclusions can be drawn from molecular dynamics simulation: five SARS-CoV-2 variants of concern have enhanced binding ability of RBD to host receptor,and the delta and omicron variants have the strongest binding ability to host.After the binding of SARS-CoV-2 to the host receptor ACE2,the fusion of the viral and host cell membranes will be performed.At the end of this thesis,the key proteins in the fusion process of SARS-CoV-2 and host membranes were introduced,and the fusion inhibitor EK1 was improved.The binding affinity of the newly optimized inhibitor to heptad repeat 1(HR1)of spike protein is stronger than that of original EK1 to HR1,and this work are expected to provide useful references for the prevention of SARS-CoV-2 and the treatment of COVID-19.