Assessing Helical Protein Interfaces for Inhibitor Design

Abstract

Structure-based design of synthetic inhibitors of protein–protein interactions (PPIs) requires adept molecular design and synthesis strategies as well as knowledge of targetable complexes. To address the significant gap between the elegant design of helix mimetics and their sporadic use in biology, we analyzed the full set of helical protein interfaces in the Protein Data Bank to obtain a snapshot of how helices that are critical for complex formation interact with the partner proteins. The results of this study are expected to guide the systematic design of synthetic inhibitors of PPIs. We have experimentally evaluated new classes of protein complexes that emerged from this data set, highlighting the significance of the results described herein.