Construction of PROTAC-Mediated Ternary Complex Structure Distribution Profiles Using Extensive Conformational Search

Proteolysis-targeting chimeras (PROTACs) are heterobifunctional small molecules that recruit E3 ubiquitin ligases to a target protein and induce its ubiquitination by forming a ternary complex. For rational PROTAC design, computational methods that provide molecular insights into these association structures are required. In this study, we attempted extensive conformational search of PROTAC-mediated ternary complex structures using enhanced conformational sampling methods. Stable conformations were extracted from the molecular dynamics’ ensembles by constructing Markov state models as their distribution profiles. These insights provided rational structure–activity relationships for PROTACs through the protein-ligand interaction analysis and the modeling of the ubiquitination system.