Transition path sampling (TPS), which involves finding probable paths connecting two points on an energy landscape, remains a challenge due to the complexity of real-world atomistic systems. Current machine learning approaches rely on expensive training procedures and under-utilize growing quantities of atomistic data, limiting scalability and generalization. Generative models of atomistic conformational ensembles sample temporally independent states from energy landscapes, but their application to TPS remains mostly unexplored. In this work, we address TPS by interpreting candidate paths as trajectories sampled from stochastic dynamics induced by the learned score function of generative models, namely denoising diffusion and flow matching. Under these dynamics, finding high-likelihood transition paths becomes equivalent to minimizing the Onsager-Machlup (OM) action functional, enabling us to repurpose pre-trained generative models for TPS in a zero-shot fashion. We demonstrate our approach on a Müller-Brown potential and several fast-folding proteins, where we obtain diverse, physically realistic transition pathways, as well as tetrapeptides, where we demonstrate successful TPS on systems not seen by the generative model during training. Our method can be easily incorporated into new generative models, making it practically relevant as models continue to scale and improve.

Simulating rare events, such as the transformation of a reactant into a product in a chemical reaction typically requires enhanced sampling techniques that rely on heuristically chosen collective variables (CVs). We propose using differentiable simulations (DiffSim) for the discovery and enhanced sampling of chemical transformations without a need to resort to preselected CVs, using only a distance metric. Reaction path discovery and estimation of the biasing potential that enhances the sampling are merged into a single end-to-end problem that is solved by path-integral optimization. This is achieved by introducing multiple improvements over standard DiffSim such as partial backpropagation and graph mini-batching making DiffSim training stable and efficient. The potential of DiffSim is demonstrated in the successful discovery of transition paths for the Muller-Brown model potential as well as a benchmark chemical system - alanine dipeptide.