Protein interactions design.

Abstract

Protein-protein interactions are key to many biological processes. Engineering these interactions aids in the creation of vaccines, protein inhibitors, new synthetic reactants, etc. Therefore, leading to the development of different computational design strategies. However, these design strategies have thus far failed to accurately capture the energy functions that contribute to the stability of protein interfaces. The aim of this project is to devise a general computational design strategy, which incorporates native residues that are involved in hydrogen bonds. In designing these interactions, we hope to accurately reproduce the residue-residue interactions, including inter-protein hydrogen bonding. The first step of the design protocol is to define key surface residues that are involved in an interaction. The definition of these residues was another challenge faced in protein interface design. In our design protocol, we used a general cutoff distance of 4.75Å obtained by taking into consideration hydrogen bond residues and solvent accessibility. The design protocol was benchmarked and then tested by designing an MDM2 inhibitor. The suggested candidates were observed to retain at least half of the native hydrogen bonds. Therefore, we believe that, with further in-depth analysis, this computational design strategy would be a useful tool in designing protein interfaces.