Designing Cooperative Molecular Glues for FKBP12-MAPRE1 with Enhanced-Sampling Molecular Dynamics Simulations.
- 1Department of Chemistry and Applied Biosciences, ETH Zurich, Vladimir-Prelog-Weg 2, Zurich8093, Switzerland.
- 2Novartis Biomedical Research, Novartis Campus, Basel4002, Switzerland.
Abstract
Molecular glues (MGs) offer a unique modality for inducing protein-protein interactions (PPIs), yet their rational design is often hindered by the limitations of static structural data. Here, we present a computational pipeline for the design of cooperative MGs for the FKBP12-MAPRE1 system using replica exchange with solute scaling (REST2) for enhanced sampling in molecular dynamics (MD) simulations. By sampling the conformational ensembles of binary and ternary complexes, we identified a "stabilized configurational space" that facilitates ternary-complex formation through a combination of conformational selection and induced-fit mechanisms. Based on the simulations, we developed a model that correlates PPI induction information from the simulations with the experimental cooperativity. This model was subsequently used to select and rank a small library of compounds prospectively, of which five were selected for synthesis and testing. Three of the five new compounds exhibited apparent cooperativity equal to or greater than that of the best previously known variants. This study demonstrates that targeting shared configurations within dynamic ensembles is a viable strategy for the rational optimization of cooperative molecular glues.
Related
- Development of A Modeling Framework for Characterizing Protein–Polymer Bioconjugates with Enhanced Sampling Molecular Dynamics Simulations
- Light Martini water accelerates sampling in coarse-grained molecular dynamics simulations
- Comparative Conformational Sampling of Apo Adenylate Kinase by Enhanced Molecular Dynamics and a Sequence-Based Generative Ensemble Model
- Gaussian accelerated Molecular Dynamics - Thermodynamic Integration (GaMD-TI): Improved alchemical free energy calculations with enhanced sampling
- Enhanced diffusion sampling: Efficient rare event sampling and free energy calculation with diffusion models
BibTeX
@article{chen2026designing,
title = {{Designing Cooperative Molecular Glues for FKBP12-MAPRE1 with Enhanced-Sampling Molecular Dynamics Simulations.}},
author = {Shu-Yu Chen and Riccardo Solazzo and Marianne Fouché and Hans-Jörg Roth and Birger Dittrich and Sereina Riniker},
journal = {Journal of the American Chemical Society},
year = {2026},
month = oct,
doi = {10.1021/jacs.6c12127},
url = {https://europepmc.org/article/MED/42913579},
note = {CC BY},
}
RIS
TY - JOUR
TI - Designing Cooperative Molecular Glues for FKBP12-MAPRE1 with Enhanced-Sampling Molecular Dynamics Simulations.
AU - Shu-Yu Chen
AU - Riccardo Solazzo
AU - Marianne Fouché
AU - Hans-Jörg Roth
AU - Birger Dittrich
AU - Sereina Riniker
PY - 2026
DA - 2026/10/01
JO - Journal of the American Chemical Society
DO - 10.1021/jacs.6c12127
UR - https://europepmc.org/article/MED/42913579
AB - Molecular glues (MGs) offer a unique modality for inducing protein-protein interactions (PPIs), yet their rational design is often hindered by the limitations of static structural data. Here, we present a computational pipeline for the design of cooperative MGs for the FKBP12-MAPRE1 system using replica exchange with solute scaling (REST2) for enhanced sampling in molecular dynamics (MD) simulations. By sampling the conformational ensembles of binary and ternary complexes, we identified a "stabilized configurational space" that facilitates ternary-complex formation through a combination of conformational selection and induced-fit mechanisms. Based on the simulations, we developed a model that correlates PPI induction information from the simulations with the experimental cooperativity. This model was subsequently used to select and rank a small library of compounds prospectively, of which five were selected for synthesis and testing. Three of the five new compounds exhibited apparent cooperativity equal to or greater than that of the best previously known variants. This study demonstrates that targeting shared configurations within dynamic ensembles is a viable strategy for the rational optimization of cooperative molecular glues.
SN - 0002-7863
SN - 1520-5126
ER -