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. However, the structural dynamics underlying the complex formation and degradation efficiency remain unclear. In this study, we attempted an extensive conformational search using the parallel cascade selection molecular dynamics (PaCS-MD) and outlier flooding (OFLOOD) method for PROTACs differing in linker length. Markov state models revealed that while all PROTACs share a common low free-energy state, their structural distribution profiles differ significantly. These results suggest that linker-dependent conformational distribution profiles modulate degradation activity and cooperativity, offering mechanistic insights into rational PROTAC design.