Prediction and Design of Molecular Recognition
Tanja Kortemme · The FASEB Journal · 2006
A promising approach to delineate complex protein interaction networks and to uncover principle underlying biological regulation is to build tools that can alter molecular recognition processes in a predictive and tunable manner. As a first step towards this goal, we have developed a computational all‐atom model for the prediction and design of protein‐mediated interactions. Using this model, we have developed computational strategies for the redesign of protein complexes to generate new pairs of interacting proteins. The design of a new domain‐domain interface generated by fusing domains from distantly related proteins resulted in the creation of an artificial DNA cleaving enzyme. More recently, we have applied computational approaches to engineer specificity switches in protein‐protein interfaces. We experimentally demonstrated the alteration in specificity both in vitro and in the biological context in living cells, and confirmed the computational model by crystallographic analysis of several designed interfaces. Despite the significant approximations made in computational protein design methods, these results indicate that these strategies may contribute to the engineering of regulatory networks mediated by protein‐protein interactions.