Characterization of PROTACs by Ternary Complex Landscape Exploration using Monte Carlo simulations

Abstract

PROTACs (Proteolysis-Targeting Chimeras) have emerged as a powerful modality for targeted protein degradation, yet their optimization still relies heavily on trial-and-error methods. A key factor in PROTAC degradation efficiency is the formation of the ternary complex (TC) between the PROTAC and its target proteins. However, due to their dynamic nature, PROTAC-mediated TCs can adopt multiple conformations, making their characterization challenging. Computational methods that account for this flexibility can provide more accurate predictions aligned with experimental results. Here, we explore the dynamic nature of TCs by analyzing their energy landscapes using protein-protein docking coupled with Monte Carlo sampling. This approach enables the identification of energetically relevant TC conformations, including those observed in experimental crystal structures, and allows estimation of thermodynamic and kinetic stability, as shown for a set of VHL-WDR5 PROTACs. Insights from these landscapes could support the screening and optimization of tens of similar PROTACs based on TC stability.