Computational studies of protein–peptide interactions with systematic mutation of residues

Abstract

The interactions between proteins and peptides in aqueous solution have been simulated using a molecular dynamics procedure with the systematic mutation of residues. An implicit solvent model has been used in post-processing to calculate the free energy of each of the complex, protein and peptide in solution and, subsequently, the binding free energy. Entropic contributions to the binding free energy have been estimated using classical ideal gas thermodynamics. A program has also been developed that systematically mutates each residue of the interacting peptide to alanine and determines the effect on the binding free energy. The interaction between the oncoprotein Mdm2 and the tumour suppressor peptide p53 has been used to test the method and reasonable agreement has been found with experiment and previous theoretical studies. The method has been extended to investigate the interaction between D10-p1, a mirror image D-peptide and potential Human Immunodeficiency Virus HIV-1 inhibitor, and IQN17, a model protein representing a potential drug target in the HIV-1 cell–cell fusion process. The key residues involved in the binding in each protein–peptide system have been identified and quantitative information on the significant factors in their importance have been obtained and compared with available experimental data.