Design of Protein-Protein Interactions with a Novel Ensemble-Based Scoring Algorithm

摘要

Protein-protein interactions (PPIs) are vital for cell signaling, protein trafficking and localization, gene expression, and many other biological functions. Rational modification of PPI targets provides a mechanism to understand their function and importance. However, PPI systems often have many more degrees of freedom and flexibility than the small-molecule binding sites typically targeted by protein design algorithms. To handle these challenging design systems, we have built upon the computational protein design algorithm K* [8,19] to develop a new design algorithm to study protein-protein and protein-peptide interactions. We validated our algorithm through the design and experimental testing of novel peptide inhibitors. Previously, K* required that a complete partition function be computed for one member of the designed protein complex. While this requirement is generally obtainable for active-site designs, PPI systems are often much larger, precluding the exact determination of the partition function. We have developed proofs that show that the new K* algorithm combinatorially prunes the protein sequence and conformation space and guarantees that a provably-accurate e-approximation to the K* score can be computed. These new proofs yield new algorithms to better model large protein systems, which have been integrated into the K* code base.