Theoretical study of the amino acid interactions in the binding region of the trypsin–pancreatic trypsin inhibitor complex

The meaningful interactions in the contact region of the trypsin–pancreatic trypsin inhibitor complex have been evaluated using free energy simulation methods and appropriate thermodynamic cycles. Consequently, mutations on a few selected residues were performed to destroy the specificity of these interactions preserving the three-dimensional structure of the original species; therefore, the original and mutated residues involved had to be similar from a topological point of view but with opposite chemical properties. The thermodynamic perturbation, conventional thermodynamic integration, thermodynamic integration with end-point perturbational correction and thermodynamic integration conjugated with the extrapolation method of Brooks formalisms have been used in these calculations. The results obtained, with these four alternative approaches, are in reasonable, mutual agreement and reveal that the strength of a specific interaction increases with the charge separation between the amino acid residues involved, and with the hydrophilicity of the surrounding environment.