Unsupervised Thermodynamics of Molecular Diffusion Models: Action-Operator Semantics and Auditable Free-Energy Readout

Abstract:Diffusion models are increasingly utilized for modeling molecular structures and conformational ensembles, yet the thermodynamic meaning of their learned representations and scores remains elusive. To resolve this ambiguity, we introduce a mathematically consistent action-operator framework natively compatible with diffusion models. By defining a fixed molecular environment as a base action $S_0(x)$ and an alchemical perturbation as an operator $O(x)$, standard diffusion noising induces effective noised actions and operators whose gradients and alchemical derivatives are directly represented by the model's learned fields. This rigorous self-consistency enables a ``noisy operator bridge'' capable of reading out free-energy differences ($\Delta F$) from endpoint ensembles and per-frame evaluations. In controlled experiments on alanine dipeptide systems, we show that incorporating physical inductive biases enables partial recovery of the base action and perturbation operator. When applied to a challenging C6-H to C6-F ligand-pocket nonbonded perturbation (185L/IND) with negligible phase-space overlap, our supervised bridge estimates the alchemical $\Delta F$ within approximately $1\ k_\mathrm{B}T$ of a stable 19-state MBAR reference. Finally, we demonstrate that endpoint coordinates and binary labels alone are sufficient to partially recover the operator shape and a centered free-energy scale without any force or action supervision. This work provides a rigorous path toward transforming generative molecular diffusion models from black-box coordinate samplers into auditable thermodynamic estimators.

Chemical Physics (physics.chem-ph); Statistical Mechanics (cond-mat.stat-mech); Artificial Intelligence (cs.AI)

arXiv:2606.30687 [physics.chem-ph]

(or arXiv:2606.30687v2 [physics.chem-ph] for this version)

https://doi.org/10.48550/arXiv.2606.30687 Focus to learn more arXiv-issued DOI via DataCite

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