Stochastic Control Policies for Robust Molecular Transition Path Sampling

Transition path sampling (TPS) aims to efficiently generate rare molecular transition trajectories between metastable states and is essential for understanding biomolecular mechanisms. Beyond traditional molecular dynamics (MD)-based sampling, machine learning has become central to state-of-the-art TPS. One major class of methods learns control forces during explicit MD rollouts. By preserving the underlying molecular dynamics, these methods tend to produce more physically plausible trajectories than endpoint-conditioned generators that construct paths directly. However, rollout-based control methods have been reported to exhibit unstable and strongly seed-dependent performance. We recast rollout-based control as learning a path-space proposal distribution and investigate stochasticity placement as a design choice for improving exploration and optimization robustness. We develop two stochastic policies: FS-TPS, which directly parameterizes a state-dependent Gaussian distribution over the control policy output, and LaS-TPS, which samples a compact latent control variable and decodes it into structured, cross-atom-correlated force variation. We conduct extensive multi-seed experiments on three biomolecular systems of increasing size: alanine dipeptide, chignolin, and BBL, a fast-folding protein. Stochastic policies consistently improve transition success and path quality over deterministic-policy baselines while substantially reducing sensitivity to random initialization.

Transferable Implicit Solvent Machine Learning Potential for Drugs and Proteins Approaching Ab Initio Accuracy

Machine learning interatomic potentials (MLPs) have revolutionized atomistic modeling, offering the potential to replace traditional methods like Density Functional Theory (DFT). However, inference time of MLPs is orders of magnitude slower than that of classical force fields, hindering real-world applications for biomolecular systems that require timescales of microseconds and beyond. Implicit solvent MLPs can address this issue, but are faced with data challenges associated with coarse-grained modeling. Consequently, previous approaches relied on empirical force field data, thereby inherently limiting the MLP's accuracy. Here, we introduce the Transferable Water Implicit Network (TWIN), an implicit water MLP parametrized entirely by an Equivariant Graph Neural Network and trained solely on ab initio and experimental labels. We demonstrate TWIN's transferability across drug-like molecules, peptides, and proteins, achieving excellent results on ab initio and experimental crystallographic and NMR benchmarks, consistently outperforming previous machine-learning-based implicit solvent or coarse-grained models. Furthermore, TWIN closely matches DFT-based explicit solvent MLPs while providing a two-order-of-magnitude faster timestep evaluation, paving the way for efficient ab initio-level modeling of biomolecular systems in aqueous environments.