Ternary Complex Geometry and Lysine Positioning Guide the Generation of PROTAC-Induced Degradable Complexes

Targeted protein degradation via
PROTACs (PROteolysis
TArgeting
Chimaeras) has transformed drug discovery by enabling the elimination
of disease-driving proteins, including those previously considered
undruggable. However, rational PROTAC design remains hindered by the
lack of systematic approaches to evaluate the geometry of ternary
complexes, ubiquitination feasibility, and the influence of linker
architecture on degradation potential. Here, we present an integrative
computational framework that addresses these challenges by combining
ternary complex generation, pairwise RMSD-based clustering, full CRL2VHL RING-like complex modeling, lysine proximity analysis,
and structure-guided dynamics. As a representative system, we applied
this workflow to PTP1B, a phosphatase implicated in oncogenic signaling
yet long considered therapeutically challenging. Over 6900 ternary
complex poses were generated across diverse linker designs and systematically
filtered using custom Python scripts that automate pose clustering
and lysine-to-E2 distance evaluation. Critical ternary complexes were
subjected to molecular dynamics simulations, PCA, TICA, and Markov
state modeling to reveal degradation-competent conformations and dynamic
transitions. We additionally assessed AlphaFold-Multimer and Arg69-guided
docking approaches. AlphaFold-Multimer produced few lysine-accessible
poses, whereas Arg69-guided docking enriched degradation-competent
geometries via biologically relevant interactions. This framework
offers a mechanistically grounded and generalizable strategy for rational
PROTAC development across protein targets.