Investigating Dynamics of HLA Molecules by Energy Dissipation

Abstract

T cell mediated immunity is one of the major defense mechanisms in higher organisms against microbial pathogens. Immune response is triggered when T cells recognize foreign material from the fractions of the antigen, ceased or deficient proteins and peptides from viruses, which are presented with pMHC molecules. Many alleles and sub-types of these proteins are found to be associated with autoimmune diseases; hence it is crucial to understand the mechanism of signal transduction within these complexes both from structural and immunological points of view. Proteins are open systems where external energy can be transferred with the help of intermolecular interactions since proteins are dynamic and the residues are constantly fluctuating. Perturbation of specific residues enable us to determine a possible signaling network in proteins using external energy as an input while focusing on the dispersion of this energy between residues throughout the structure. In this study, in order to obtain further details on the stability of the peptide and to investigate the presence of a possible binding network in HLA molecules, we applied an energy dissipation method. Molecular dynamics simulations were performed with and without energy perturbation using NAMD software with CHARMM27 force field. Energy perturbation was applied by increasing the velocity of a chosen residue at the desired time step of the initial MD simulation. Energy change of each residue was calculated based on the total energy difference between the perturbed and the reference simulations. At the end, residue response times, corresponding to the time of the response of a residue after the perturbation of another chosen residue, are obtained. Key residues determined by these response times enlighten both the similarities and the differences between the HLA alleles and their binding properties.