Exploring PROTAC cooperativity with coarse-grained alchemical methods

TL;DR

This paper introduces a coarse-grained computational framework to model PROTAC cooperativity, capturing key principles and dependencies, with potential for aiding PROTAC design despite current limitations in quantitative accuracy.

Contribution

The authors develop a novel coarse-grained alchemical method to study PROTAC-induced protein interactions, providing insights into cooperativity mechanisms and linker length effects.

Findings

Optimal linker length arises from configurational entropy.

Cooperativity depends on protein charges and shapes.

Minimal parameterization captures fundamental principles.

Abstract

Proteolysis targeting chimera (PROTAC) is a novel drug modality that facilitates the degradation of a target protein by inducing proximity with an E3 ligase. In this work, we present a new computational framework to model the cooperativity between PROTAC-E3 binding and PROTAC-target binding principally through protein-protein interactions (PPIs) induced by the PROTAC. Due to the scarcity and low resolution of experimental measurements, the physical and chemical drivers of these non-native PPIs remain to be elucidated. We develop a coarse-grained (CG) approach to model interactions in the target-PROTAC-E3 complexes, which enables converged thermodynamic estimations using alchemical free energy calculation methods despite an unconventional scale of perturbations. With minimal parameterization, we successfully capture fundamental principles of cooperativity, including the optimality of intermediate PROTAC linker lengths that originates from configurational entropy. We qualitatively characterize the dependency of cooperativity on PROTAC linker lengths and protein charges and shapes. Minimal inclusion of sequence- and conformation-specific features in our current forcefield, however, limits quantitative modeling to reproduce experimental measurements, but further development of the CG model may allow for efficient computational screening to optimize PROTAC cooperativity.