Free energy Estimation on Any State Space

Estimating free energy differences quantifies thermodynamic preferences in molecular interactions, which is central to chemistry and drug discovery. Despite fruitful progress, existing methods still face key limitations: classical computational approaches remain prohibitively expensive due to their reliance on extensive molecular dynamics simulations, while deep learning-based methods are constrained by either less-expressive generative models or input dimensions tied to a specific system, resulting in negligible generalization. To address these challenges, we propose CARD, a generative framework that employs a novel radix-based decomposition to bijectively convert 3D coordinates into mixed discrete-continuous sequences, enabling coarse-to-fine autoregressive modeling with enhanced expressiveness. Notably, the model corresponds to a distribution with zero free energy, serving as a proposal for absolute free energy computation of arbitrary systems without relying on alchemical pathways. Experiments across diverse tasks demonstrate that CARD matches the accuracy of classical computational methods on unseen systems with diverse topologies, while achieving an approximately 40-fold speedup in inference.

The last decade has seen the development of powerful methods for learning complex structure from high-dimensional data. These advances have brought to the foreground fundamental connections between subdisciplines of physics, applied mathematics, and machine learning. In this review, we bring together some of these ideas, often expressed in different languages, to highlight a conceptual thread that links five distinct fields: control theory, optimal transport, probabilistic inference, non-equilibrium thermodynamics, and machine learning. A common theme is the optimization of free-energy-like functionals under dynamical or statistical constraints. We offer a guided tour through this thread and present selected applications in reinforcement learning, variational inference, and generative modeling. The review does not assume prior familiarity with these topics, and begins with principles originating from physics.

Many modern generative modeling methods, including diffusion models, normalizing flows, and flow matching, estimate transport maps or plans between distributions without explicitly targeting an optimal transport (OT) map. In applications like generative modeling, the transport cost itself is irrelevant, and this makes it natural to target maps which are more tractable from either a statistical or computational standpoint. In this short note, we formalize the task of estimating any valid transport map in a rigorous minimax framework. One consequence of this framing is that it yields sample complexity lower bounds for any method whose learned object is evaluated as a transport map or plan, including flow matching and diffusion-based generative models, in settings where direct analysis would be challenging due to the analytic complexity of the methods and their target maps. We observe that, under standard, though strong, stability assumptions from the OT literature, estimating any valid transport map is statistically as hard as estimating the OT map. We complement these results with some examples showing that when these stability assumptions fail, alternative transport maps can be learned substantially more accurately than the OT map. Our minimax framing provides a rigorous foundation for understanding the statistical limits of modern transport-based generative methods and clarifies when targeting sub-optimal maps can provide real statistical advantages.