Binding Free Energy Between Antigen Peptide And HLA-A~*0201 Molecule Based On MM/PBSA Method

CTL epitope based epitope vaccine was prepared, which was one of significant methods for the immunotherapy of malignant tumor that was detrimental to human health. During the presentation of endogenous antigens of cellular immunity, CTL epitope containing antigen can be presented to target cell surface by binding with MHC-I molecule first, so as to be identified by CTL cells. Therefore, the investigation of MHC-I molecule binding with antigen peptide was of great significance to the identification of CTL epitope.Human MHC molecules was called HLA molecules, of which, the HLA I molecules were classified into HLA-A, HLA-B and HLA-C based on the gene encoding loci. Previous investigations showed that HLA-A~*0201 was the most widely distributed HLA molecule among various races. Therefore the identification of CTL restricting epitope in HLA-A~*0201 molecules was crucial to the immunotherapy of malignant tumor of different races.In the present study, HLA-A~*0201 molecule and binding peptide of antigen (with the sequence of LLFGYPVYV) were selected as receptor and ligand for protein binding process so as to calculate the binding free energy. Firstly, the binding process was simulated via MM/PBSA combined with molecular dynamics method, and the binding free energy then obtained was-157.84 kJ·mol-1, the relative error of which compared with experimental value was 13.94%. To improve the binding free energy calculation accuracy, QM/MM algorithm in combination with MM/PBSA means was introduced to simulate the binding process, and the calculated binding free energy value was-173.68 kJ·mol-1, the relative error of which compared with experimental value was just 5.31%. The results indicated that promotion of the accuracy of binding free energy calculated based on MM/PBSA method was well resolved through either the QM/MM established, or the simulation process designed as well as the simulation parameters selected in the present study. Finally, the conclusion was drawn, that the most important driving force for HLA-A~*0201 binding with antigen peptide was van der Waals force in addition to non-polar solvation effect, by the analysis of energy terms in the binding free energy formulation.