Research And Application Of Calculation Method Of Protein-protein Binding Free Energy

Protein-protein interaction is an important way for proteins to play physiological roles in organisms.This paper focuses on the effect of protein residue mutation on the binding free energy of protein-protein complex through molecular dynamics simulation method.This article conducted the following researches:1.First,using ASGBIE method to calculate the hotspot residues of the H4K20me2/53BP1-TTD complex.Secondly,a de-methylation method is proposed to predict relative binding free energies between 53BP1 and different methylated states of H4K20.Finally,the tri-methylated and non-methylated H4K20/53BP1-TTD complexes are found to be dynamically unstable,explaining the experimental finding that neither can bind to 53BP1.The present work provides an important theoretical basis for our understanding of histone methylations of H4K20 and their recognition mechanism by DNA repair factor 53BP1.2.The minimized de-methylation method proposed in the first work was improved.Based on a series of histone methylation complexes,the improved method was systematically tested and compared with TI method.The results show that the minimized de-methylation method based on GB^OBC model I solvation model has the best applicability when calculating the difference of binding free energy between different methylation states of the same system.3.Performing molecular dynamics simulation of these binding complexes and calculated their binding free energies using ASGB method.The MD simulation and hotspot residues analysis showed that the lower binding affinity of SARS-CoV to ACE2vs SARS-CoV-2 to ACE2 can be explained by different hotspot interactions in these two systems.We also found that the lower binding affinity of RaTG13 to ACE2 is mainly due to a mutated residue(D501)which resulted in a less favorable complex formation for binding.The present work provided important theoretical basis for understanding the molecular mechanism in coronavirus spike protein bindings to human ACE2.4.The calculations show that five major mutations(N501Y,E484K,L452R,T478K and K417N),first reported in Alpha,Beta,Gamma and Delta variants,all increase the binding of the S protein to ACE2(except K417N),consistent with the experimental findings.Comparison of several different computational methods for binding free energy calculation of these mutants was made.The results show that the ASGB method is an efficient and reliable method for these binding free energy calculations due to mutations.Finally,we also studied an additional eight mutations of the Omicron variant that are located on the interface of the RDB and have not been reported in other VOCs.Our study showed that most of these mutations enhance the binding of the S protein to ACE2.The above computational simulation study provided theoretical basis for understanding the molecular mechanism of corresponding experimental results,and can give some assistance to the experiment.These researches developed the calculation method of protein-protein binding free energy,and also provided foundation for follow-up researches.