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bioRxiv · 10.64898/2026.09.24.754053

Pair-complete structural gating enables Pareto optimization of de novo cyclic peptides with preserved binding geometry and improved developability

Hou, Y.·Zhang, Y.·Liu, Z.·Peng, X.·Yusupujiang, M.·Xu, Y.·Hu, J.·Yang, S.
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Abstract

Cyclic peptides can engage extended protein interfaces, but sequence changes that improve developability often disrupt the selected target-bound geometry. Existing property-guided design methods lack a principled way to preserve this geometry during local multiproperty optimization. Here we present RF-PepTune, which separates structural eligibility from property prioritization. Before any property score is queried, RF-PepTune evaluates single substitutions and all position-distinct pairs induced by admitted substitutions to build a parent-specific, pair-complete admission graph. Pareto Monte Carlo tree search then optimizes predicted permeability, solubility, non-fouling, and low-haemolysis scores exclusively within this graph, and selected sequences undergo full structural re-evaluation. In a matched three-arm comparison of 334 parents across MDM2, GABARAP, and MCL1, joint property-structure success rose from 10.2% without admission to 51.5% with single-substitution admission and 77.5% with pair-complete admission; pair-complete gating improved success by 26.0 percentage points over single-substitution gating (95% CI, 20.7-31.4). Property-positive but structure-failing endpoints fell from 88.3% to 9.3%. In a separate target-balanced set, all 90 prioritized outputs improved all four model-native scores while satisfying prespecified structural criteria. This work establishes pairwise structural gating as a general strategy for constrained multi-objective molecular optimization.

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Hou, Y., Zhang, Y., Liu, Z., Peng, X., Yusupujiang, M., Xu, Y., Hu, J., Yang, S.. 2026-09-29. Pair-complete structural gating enables Pareto optimization of de novo cyclic peptides with preserved binding geometry and improved developability. https://doi.org/10.64898/2026.09.24.754053

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