VESPER: Online Learning of Free Energies with a Multi-Tempered Variational Objective

원문 초록

Computing molecular free-energy landscapes over collective variables (CVs) is central to understanding molecular mechanisms, but poses a difficult learning problem without training data available a priori. Samples of the marginal CV distribution must be generated by molecular dynamics (MD), whose trajectories can remain trapped in metastable states and rarely cross the free-energy barriers governing conformational changes or chemical reactions. We introduce VESPER, which couples the generation of these samples to neural-network-driven free-energy learning: MD supplies configurations for learning, while the evolving model biases the MD to accelerate exploration and generate further training data. VESPER minimizes a single variational objective that is convex in the free energy and can combine several tempering levels, each flattening the free-energy landscape to promote barrier crossing. Every level has the same physical free energy as its minimizer, allowing data from all levels to train one shared model without reweighting. Learning uses the difference in mean parameter gradients between biased MD configurations and auxiliary walkers that explore the flattened model in CV space. We prove conditional convergence of the coupled overdamped population dynamics without replica exchange under log-Sobolev and Polyak-Lojasiewicz assumptions. VESPER matches or improves on established enhanced-sampling methods on alanine dipeptide and yields self-consistent free-energy reconstructions from three to six CVs on alanine tetrapeptide. For methane dehydrogenation on Ni(511) with a machine-learned interatomic potential, it recovers two-CV Boltzmann marginals and a reactant-to-saddle free-energy difference along a three-CV path, both qualitatively consistent with the lower-dimensional reference. It also samples RMSD-defined folded and unfolded regions of chignolin while biasing seventeen CVs.