Hamiltonian replica exchange augmented with diffusion-based generative models and importance sampling to assess biomolecular conformational basins and barriers (2505.08357v1)

Abstract: Enhanced sampling techniques are essential for exploring biomolecular conformational dynamics that occur on timescales inaccessible to conventional molecular dynamics (MD) simulations. This study introduces a framework that combines Hamiltonian replica exchange (REST2) with denoising diffusion probabilistic models (DDPMs) and importance sampling to enhance the mapping of conformational free-energy landscapes. Building on previous applications of DDPMs to temperature replica exchange (TREM), we propose two key improvements. First, we adapt the method to REST2 by treating potential energy as a fluctuating variable. This adaptation allows for more efficient sampling in large biomolecular systems. Second, to further improve resolution in high-barrier regions, we develop an iterative scheme combining replica exchange, DDPM, and importance sampling along known collective variables. Benchmarking on the mini-protein CLN025 demonstrates that DDPM-refined REST2 achieves comparable accuracy to TREM while requiring fewer replicas. Application to the enzyme PTP1B reveals a loop transition pathway consistent with prior complex biased simulations, showcasing the approach's ability to uncover high-barrier transitions with minimal computational overhead with respect to conventional replica exchange approaches. Overall, this hybrid strategy enables more efficient exploration of free-energy landscapes, expanding the utility of generative models in enhanced sampling simulations.