# Robust Biomolecular Complex Design Across Protein Conformational Landscapes

arXiv: https://arxiv.org/abs/2609.33726 · HTML: https://mlsanity.com/paper/2609.33726/

## Key facts

- No citing papers in the map yet (data through 14 Oct 2026).
- Builds on 4 of its 48 references that are in the map.
- First posted on arXiv 27 Sep 2026.

## Builds on (most cited first, 4 of 4)

- [Cross-Modality Attack Boosted by Gradient-Evolutionary Multiform Optimization](https://mlsanity.com/paper/2409.17977/) (2024)
- [Med-Scout: Curing MLLMs' Geometric Blindness in Medical Perception via Geometry-Aware RL Post-Training](https://mlsanity.com/paper/2601.23220/) (2026)
- [Don't Retrain, Just Reuse: Recovering Dual-Target Molecules from Single-Target Diffusion Models](https://mlsanity.com/paper/2605.25681/) (2026)
- [Can Broad Biomedical Knowledge be Contextualized into Scenario-Grounded Propositions?](https://mlsanity.com/paper/2605.27082/) (2026)

## Abstract (arXiv)

Proteins populate conformational ensembles, yet structure-based biomolecular design typically optimizes candidates against a single target conformation. Consequently, a candidate that fits one state can lose favorable interactions or develop steric clashes when the target adopts another. We introduce FlexEvo, a model-agnostic evolutionary framework that adapts candidates once at inference time from a single target conformation to improve compatibility with alternative natural conformations unseen during adaptation, without retraining the source model or requiring a conformational ensemble. FlexEvo casts cross-state adaptation as geometry-constrained bi-objective optimization, balancing preservation of input-state interactions against robustness to plausible conformational perturbations. To limit the search space and reduce invalid structural edits, geometry-derived FlexBoxes define protected anchor regions, adaptable regions for local exploration, and forbidden regions for clash avoidance. A unified all-atom representation supports topology-preserving adaptation across diverse binder categories, while Pareto selection preserves nondominated candidates across the two objectives. We evaluate FlexEvo across multiple generation baselines and nine representative binder categories spanning diverse molecular sizes and structural topologies. FlexEvo reduces the category-balanced mean relative performance degradation from 47.8% to 4.4%, while adding only 1.4--3.1 minutes of adaptation per sample. These results establish single-state inference-time adaptation as a practical route toward robust biomolecular complex design across protein conformational landscapes.