In Silico Modeling and Scoring of PROTAC-Mediated TernaryComplex Poses

Proteolysis targeting chimeras (PROTACs) aremolecules that induce protein degradation via formation of ternarycomplexes between an E3 ubiquitin ligase and a target protein. Therational design of PROTACs requires accurate knowledge of thenative configuration of the PROTAC-induced ternary complex.This study demonstrates that native and non-native ternarycomplex poses can be distinguished based on the pose occupancytime in MD, where native poses exhibit longer occupancy times atboth room and higher temperatures. Candidate poses aregenerated by MD sampling and pre-ranked by classic MM/GBSA. A specific heating scheme is then applied to accelerateternary pose departure, with the pose occupancy time and fractionbeing measured. This scoring identifies the native pose in allsystems tested. Its success is partially attributed to the dynamic nature of pose departure analyses, which accounts for entropic effectstypically neglected in the faster static scoring methods, while entropy plays a greater role in protein-protein than in protein-ligandsystems.

Automated summary

This study demonstrates a method to distinguish native and non-native ternary complex poses based on the pose occupancy time. Using a specific heating scheme to accelerate pose departure, the native pose can be identified accurately. The dynamic scoring method takes into account the effect of entropy and is more reliable in determining the native pose.