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oai:figshare.com:article/34045585 2026-10-01T12:08:49Z category_1 category_4 category_13 category_24 category_873 category_734 category_931 category_64 category_135 portal_63 item_type_6 month_year_10_2026

Designing Cooperative Molecular Glues for FKBP12-MAPRE1 with Enhanced-Sampling Molecular Dynamics Simulations Shu-Yu Chen (9466604) Riccardo Solazzo (22092601) Marianne Fouché (1508323) Hans-Jörg Roth (1508320) Birger Dittrich (1619110) Sereina Riniker (1450804) Biophysics Biochemistry Genetics Evolutionary Biology Chemical Sciences not elsewhere classified Biological Sciences not elsewhere classified Information Systems not elsewhere classified Cancer Computational Biology static structural data ppis ), yet cooperative molecular glues molecular dynamics viable strategy unique modality ternary complexes subsequently used study demonstrates solute scaling small library rational optimization often hindered fit mechanisms facilitates ternary experimental cooperativity cooperative mgs conformational selection conformational ensembles computational pipeline compounds prospectively complex formation 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. 2026-10-01T00:00:00Z Text Journal contribution 10.1021/jacs.6c12127.s001 https://figshare.com/articles/journal_contribution/Designing_Cooperative_Molecular_Glues_for_FKBP12-MAPRE1_with_Enhanced-Sampling_Molecular_Dynamics_Simulations/34045585 CC BY-NC 4.0