Molecular glues stabilize water-mediated hydrogen bonds in ternary complexes

TL;DR

This study uses molecular dynamics simulations to explore how molecular glues stabilize water-mediated hydrogen bonds in protein complexes, revealing their role in modulating protein flexibility and interactions.

Contribution

The paper provides new insights into the molecular mechanisms by which molecular glues stabilize protein-protein interactions through water-mediated hydrogen bonds.

Findings

Molecular glues reduce protein flexibility in certain regions.

Water-mediated hydrogen bonds are crucial for the stability of ternary complexes.

Design strategies should consider water-mediated interactions for effective molecular glue development.

Abstract

By stabilizing weak and transient protein-protein interactions (PPIs), molecular glues address the challenge of targeting proteins previously considered undruggable. Rapamycin and WDB002 are molecular glues that bind to FK506-binding protein (FKBP12) and target the FKBP12-rapamycin-associated protein (FRAP) and the centrosomal protein 250 (CEP250), respectively. Here, we used molecular dynamics simulations to gain insights into the effects of molecular glues on protein conformation and PPIs. The molecular glues modulated protein flexibility, leading to less flexibility in some regions, and changed the pattern and stability of water-mediated hydrogen bonds between the proteins. Our findings highlight the importance of considering water-mediated hydrogen bonds in developing strategies for the rational design of molecular glues.