Dynamic characteristics of proteolysis-targeting chimera systems revealed by in silico computations

Proteolysis-targeting chimeras (PROTACs) achieve irreversible clearance of target proteins by hijacking the ubiquitin-proteasome system, breaking the design paradigm of traditional inhibitory drugs. The development of computational approaches has effectively promoted the rational design of PROTACs, yet existing methods mainly focus on predicting the static structure of PROTAC systems, with methodological gaps in analyzing their dynamic characteristics. Knowing that the dynamic behaviors can dramatically influence the stability and degradation efficacy of a PROTAC system, we systematically summarize the recent progresses of using structure-based and structure-artificial intelligence-hybrid methodologies for characterizing the dynamic behaviors of PROTAC systems, with a focus on elucidating the dynamic characteristics of target protein-PROTAC-E3 ligase ternary structures and prediction of their key properties.