In Silico Modeling and Scoring of PROTAC-Mediated Ternary Complex Poses

Abstract

Proteolysis targeting chimeras (PROTACs) are bifunctional molecules that induce ubiquitination and subsequent degradation of proteins via formation of ternary complexes between an E3 ubiquitin ligase and a target protein. Rational design of PROTACs requires accurate knowledge of the native configuration of the PROTAC induced ternary complex. This study demonstrates that native and non-native ternary complex poses can be distinguished based on pose occupancy time in MD, where native poses exhibit longer occupancy times than non-native ones at both room and higher temperatures. Candidate poses are generated by MD sampling and pre-ranked by the classic MM/GBSA method. A specific heating scheme is then applied to induce ternary pose departure, generating an occupancy score and temperature score reflecting pose occupancy time and fraction. The scoring approach enables identification of the native pose in all the test systems. Beyond providing a relative rank of hypothetical poses of a given ternary system, the method could also provide empirical guidance to whether a given ternary pose is likely a native one or not. The success of the method is in part attributed to the dynamic nature of the pose departure analysis which accounts for solute entropic effects, typically neglected in the faster static pose scoring methods, while solute entropic contributions play a greater role in protein-protein interactions than in protein-ligand systems.

PROTACable Is an Integrative Computational Pipeline of 3-D Modeling and Deep Learning To Automate the De Novo Design of PROTACs

“…However, those methods require constrained templates of known ternary complex conformations 13,14 or molecular dynamics simulation. 12 In contrast, our "sum-of-parts" integrative approach 64 does not rely on any a priori knowledge of ternary complexes and starts directly from the ligand-unbound forms of the proteins. Albeit, our modeling approach may benefit from refinement particularly at the protein−protein stage, as observed from the crystal recapitulation results (Figures 2 and S1), and at the linker selection step.…”

“…Recently Liao et al, 12 Zaidman et al, 14 and Weng et al 13 leveraged computational tools to model ternary complexes. Liao et al proposed a molecular dynamics (MD)-based strategy and heating-accelerated pose change (HOPAC) rescoring method, which requires high computational resources and manual intervention.…”

“…Liao et al proposed a molecular dynamics (MD)-based strategy and heating-accelerated pose change (HOPAC) rescoring method, which requires high computational resources and manual intervention. 12 Zaidman et al provide an automated pipeline (PRosettaC), particularly at the linker insertion stage, although their method requires expert tuning based on selected atom identifiers within the PROTAC SMILES string. 14 Weng et al's approach necessitates of an established holo-form of protein complexes and user intervention for pose selection.…”