Learning Implicit Bias in Generative Spaces for Accelerating Protein Dynamics Emulation
For computational biologists and drug designers, this method accelerates protein dynamics simulations by enhancing exploration without retraining, though it is incremental over existing generative emulators and enhanced sampling techniques.
The paper introduces a history-dependent bias in the generative space of a pretrained protein dynamics emulator to improve exploration of rare states, achieving up to 37x faster coverage of low-energy states and 35% higher diversity.
Generative emulators of protein dynamics produce plausible trajectories at a fraction of the cost of molecular dynamics, but they inherit their training distribution and tend to revisit known states rather than reach rare ones under long-horizon extrapolation. Inspired by classical enhanced sampling, we introduce an implicit, history-dependent bias in the generative space of a pretrained emulator. Specifically, a history-aware score estimator augments the frozen emulator with a distance-weighted bias that steers reverse-time sampling away from previously generated structures, regularized by an environment-support term. To preserve structural validity at long horizons, a score-based refinement step re-projects drifted samples onto the data manifold using the frozen emulator. Our experiments demonstrate that the method (i) raises diversity by $35\%$ on DynamicPDB-80; (ii) on $12$ zero-shot Fast-Folding proteins, the learned bias alone reaches the unbiased emulator's coverage up to ${\sim}15\times$ faster, and pairing it with refinement reaches the coverage up to ${\sim}37\times$ faster while covering ${\sim}3\times$ as many low-energy states. Code will be released soon.