Single Amino Acid Contributions to Binding Affinity in Enzyme-Inhibitor Interactions: a Docking-Based Screening of BPTI-Beta Trypsin interaction

Enzyme-inhibitor interactions are crucial for normal functioning of many biological pathways. Point mutations in either the enzyme or the inhibitor molecule often lead to a modulation of the binding affinity (∆Go) with no major alterations in the 3D structure of the complex. The pos- sibility to screen in silico the effects of point mutations on ∆Go is of high interest, especially for protein design purposes. We have recently developed a computational protocol based on an existent rigid-body docking algorithm, which has shown a good capability to predict ∆Go changes upon mutations in protein-protein interactions. Here, we present the results obtained for the bovine pancreatic trypsin inhibitor (BPTI) and beta-Trypsin (β-Tryp) interaction. In this system, the BPTILys15 residue was replaced by eight different amino acids, hence varying the physico-chemical nature of the interface. The X-ray structure of each variant is available, as well as the effect of each substitution on the binding energetics. We compare our approach with data arising from both in vitro measurements and from another structure-based empirical approach, based on changes in solvent accessible surface areas (∆ASA) upon binding. The performance and the limitations of our approach are discussed.