Free Energy Calculation

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1 paper in the last four weeks, against 1 the four weeks before. 0.0% of all new papers.

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Latest papers 16

Sep 19, 2026physics.chem-ph

SPIBER: Reconstructing Free Energy Landscapes from Short, Unconverged Trajectories with Generative Flow Networks

Molecular systems have many degrees of freedom, but their metastable behavior can often be described by a few collective variables. Identifying these variables and estimating free energies along them from limited simulation data remains a challenging, important problem. Separate short trajectories may sample different metastable states without capturing transitions or establishing their relative equilibrium populations. For unbiased trajectories generated with the same Hamiltonian at a single temperature, alternate methods based on histogram reweighting cannot correct this imbalance. Here we present SPIBER, which combines the State Predictive Information Bottleneck (SPIB) with Generative Flow Networks (GFlowNets). SPIB uses deep learning to approximate slow degrees of freedom through a past-future information bottleneck, retaining information needed to predict future metastable states. We show that this compression limits conditional entropy variations in populated regions, allowing conditional mean potential energies, which are much easier to calculate, to be used to approximate free energy differences. Given sufficient local sampling to estimate these energies, they define the target distribution for GFlowNets, energy-based generative samplers that sample according to estimated thermodynamic stability rather than observed populations. For a particle in a radial double-well potential, for alanine dipeptide, and for the nine-residue peptide AIB9, SPIBER recovers free energy differences between sampled metastable states to within one thermal energy unit of reference values. The method combines collective-variable learning and free energy estimation in up to four latent dimensions, without requiring converged state populations or additional molecular dynamics simulations.

Venkata Sai Sreyas Adury, Pratyush Tiwary

Chemical Physics Program and Institute for Physical Science and Technology, University of Maryland, College Park 20742, USA · Biophysics Program and Institute for Physical Science and Technology, University of Maryland, College Park 20742, USA · Department of Chemistry and Biochemistry and Institute for Physical Science and Technology, University of Maryland, College Park 20742, USA +1

Free Energy Calculation Molecular Dynamics Simulation

Sep 1, 2026cond-mat.mtrl-sci

FrOGS: Discrete Neural Sampler for Independent Alloy Configurations Across Chemical Conditions

Predicting the thermodynamic properties of an alloy requires sampling its configurations across many chemical conditions and recovering free energies on a common absolute scale. Markov chain Monte Carlo (MCMC) is the standard tool, but it requires separate simulations at different conditions, and auxiliary free-energy methods such as thermodynamic integration are used to place results on a common absolute scale. Modern discrete neural samplers typically use reverse KL divergence as the objective and can be mode-seeking or biased. We present Free energy Offering Generative Sampler (FrOGS), a hybrid discrete neural sampler that couples an autoregressive model to a continuous-time Markov chain (CTMC) to be trained jointly under a single shared loss. FrOGS draws i.i.d. configurations, returns an unbiased estimate of the partition function, and gives consistent estimates of thermodynamic observables. We train a single model across a wide range of chemical conditions to produce estimates on a common absolute free-energy scale. FrOGS matches exact finite-size results on the 2D Ising model and reference phase diagrams for AgPd and CuAu, without mode collapse. We additionally compare to SEGAL, a published autoregressive baseline, and find that only FrOGS recovers the stability range of the CuAu

_3

phase.

Kyucheol Min, Elyssa Hofgard, Tess Smidt

Massachusetts Institute of Technology Cambridge, MA 02139

Free Energy Calculation Materials Science Conditional Generative Modeling

Jul 21, 2026cond-mat.dis-nn

Free energy landscape of Dense Associative Memory

Using large deviations theory, we solve and obtain a general expression for the free energy functional for a broad class of associative memories, including dense associative memories. We illustrate the method by reproducing classical results for the Hopfield model. For a finite number of patterns, we derive the temperature-dependent free energy functional for dense associative memories featuring polynomial interactions and Log-Sum-Exponential (LSE) activation. We also evaluate the disorder-averaged ground-state energy of these systems in the extensive limit. Our analytical framework reveals how memory retrieval depends on the initial state in higher-order dense networks, and gives the exact full-retrieval threshold for the LSE model. This method provides a systematic procedure for analyzing diverse, complex architectures in associative memory.

Sumedha, Abhishek Singh

School of Physical Sciences, National Institute of Science Education and Research, Bhubaneswar, P.O. Jatni, 752050, India · 2Homi Bhabha National Institute, Training School Complex, Anushakti Nagar 400094, India

Free Energy Calculation Neural Network Memorization Hopfield Networks Associative Memory

Jul 18, 2026cs.AI

Expected Free Energy as Belief-Dependent Utility for rho-POMDPs

An agent acting under partial observability must decide when to gather information and which observations are worth their cost. Standard POMDPs value information only through its eventual effect on reward. The

ρ

-POMDP framework instead rewards uncertainty reduction directly, through a belief-dependent utility

ρ

, but in practice both the choice of

ρ

and the weight placed on it are tuned by hand for every task. We show that active inference removes this tuning entirely. Minimizing Expected Free Energy (EFE) is exactly equivalent to solving a

ρ

-POMDP whose utility is expected information gain, and the exploration weight is fixed at

w=1

because the variational bound expresses pragmatic and epistemic value in the same units (nats). We prove this equivalence for observe-then-commit POMDPs and extend it to factored observation POMDPs, a broader class that covers interleaved observe-act problems such as non-destructive testing and mobile sensing, where gathering information leaves the hidden state unchanged. Experiments support the theory. Across environments ranging from the classic Tiger problem to RockSample and a new Structural Inspection benchmark with over 65,000 states, the untuned weight matches or outperforms reward-only planning at the same horizon, avoids the over-exploration of bonuses tuned per task, and sits near the reward-maximizing knee of the success-reward Pareto frontier. The practical payoff is an exploration objective that works out of the box. In applications such as fault detection and medical screening, where every test has a price and every missed fault has a cost, EFE supplies a belief-dependent utility that is derived rather than tuned.

Patrick Cooper, Alvaro Velasquez

Department of Computer Science, University of Colorado Boulder, Boulder, CO, USA

Free Energy Calculation Active Inference Value of Information Free Energy Principle Partially Observable Markov Decision Processes Decision-Making under Uncertainty

Jul 18, 2026cs.LG

Principled Direction-Free Intrinsic Motivation through Model-Free Epistemic Free-Energy Estimators

Across environments with mixed sources of uncertainty, unsupervised reinforcement learning requires intrinsic motivation that does not precommit to a particular direction of surprise. Surprise minimization is scoped by design to ``unstable'' environments. Prediction-error curiosity rewards total expected surprise, including irreducible noise. Bandit or mixture switching between surprise-minimizing and surprise-maximizing rewards reintroduces non-stationarity by construction. We propose a single intrinsic reward, stationary within each window, derived from the novelty contribution of a preference-free Expected Free Energy objective, expressed in reward-maximization form. Our claim is that parameter information gain, the expected surprise of the next state minus its irreducible part, is the appropriate intrinsic signal in both high-entropy and low-entropy components of the state space. Maximizing it seeks exactly the surprise the model can explain away. In regions of unresolved dynamics, this epistemic term drives exploration. As dynamics become resolved, the epistemic term vanishes, while an aleatoric penalty favors lower-variance transitions, all without fitting an explicit next-state predictor. A pseudocount supplies epistemic value, a probe-based penalty captures aleatoric variance, and a short-horizon gate protects informative successors. A window-based freeze of all reward-defining objects yields a stationary Bellman operator, explicit bounds on learning targets, and a conditional uniform-concentration result for the nonparametric estimators under mixing, smoothness, bandwidth, and capacity assumptions. In active-inference terms, the agent is preference-free where novelty is retained, standard likelihood ambiguity vanishes under full observability, a nonstandard transition-entropy penalty is added, and surprise minimization emerges in resolved regions of the state space.

Alireza Furutanpey, Schahram Dustdar

Coovally, Barcelona, Spain · Distributed Systems Group, TU Vienna, Austria · ICREA Barcelona, Spain

Free Energy Calculation Intrinsic Reward Methods Reinforcement Learning Free Energy Principle RL Exploration Model-Free RL+1

Jul 3, 2026physics.chem-ph

AquaGen: Scaling generative models to molecular dynamics precision on thousands of atoms

We present AquaGen, the first all-atom, explicit solvent, periodic-boundary-condition-aware generative model that produces molecular configurations from the Boltzmann distribution at a fraction of the cost of molecular dynamics (MD). This is in contrast with existing generative models that remove degrees of freedom by operating on coarse-grained, vacuum, or implicit solvent systems. Operating at this resolution allows for post-processing through force field energy evaluations and MD simulations, and enables the prediction of relevant properties in a gray-box manner (as ensemble averages of potential energy evaluations over generated samples). We demonstrate the utility of this paradigm on absolute hydration free energy (AHFE), producing estimates 4-10x faster and with comparable accuracy to standard GPU-based MD. By generating uncorrelated samples from alchemical Boltzmann distributions, we create more accurate, interpretable, and refinable ensemble predictions with calibrated uncertainty estimates, unlike regression methods which are entirely black-box predictors. Our approach also yields predictable benefits from increasing train- and test-time compute, realized by scaling model size and generating more samples, respectively. We believe that this approach demonstrates the utility of high-resolution ensemble generation for free energy estimation, with future potential to replace MD in tasks such as the prediction of lipophilicity, membrane permeability, or absolute binding free energy (ABFE) -- whose grounding and interpretability may be critical for the development of new drugs and materials.

Emmanuel Bengio, Sanjeev Raja, Yui Tik Pang +5

Valence Labs · Recursion · UC Berkeley

Free Energy Calculation Generative Modeling Molecular Generation Molecular Property Prediction

Jun 28, 2026physics.chem-ph

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

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 (

ΔF

) 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

ΔF

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.

Wenjie Xi

Department of Physics and HK Institute of Quantum Science & Technology, The University of Hong Kong, Pokfulam Road, Hong Kong, China

Free Energy Calculation Molecular Dynamics Simulation Diffusion Models

Jun 9, 2026cs.AI

Expected Free Energy-based Planning as Variational Inference

Planning under uncertainty requires agents to balance goal achievement with information gathering. Active inference addresses this through the Expected Free Energy (EFE), a cost function that unifies instrumental and epistemic objectives. However, existing EFE-based methods typically employ specialized optimization procedures that are difficult to extend or analyze. In this paper, we show that EFE-based planning can be formulated as Variational Free Energy minimization on a generative model augmented with epistemic priors. Our main result demonstrates that minimizing a Variational Free Energy functional with appropriately chosen priors yields a decomposition into expected plan costs (the EFE) plus a complexity term. This formulation reinforces theoretical consistency with the Free Energy Principle by casting planning as the same inferential process that governs perception and learning. We validate our approach on three environments of increasing complexity: a deterministic T-maze, a stochastic Reactivity Maze, and a partially observable MiniGrid DoorKey-8x8 environment. The experiments demonstrate that the epistemic priors induce information-seeking behavior, that the variational formulation yields policy-based inference outperforming plan-based methods under stochastic transitions, and that temporal factorization enables scalability to environments where existing tabular active inference methods cannot operate.

Wouter W. L. Nuijten, Thijs van de Laar, Bert de Vries

Eindhoven University of Technology, Eindhoven, the Netherlands · Lazy Dynamics B.V., the Netherlands

Free Energy Calculation Active Inference Free Energy Principle Variational Inference

May 31, 2026cs.LG

Conditioned free-energy density of proteins using unbalanced solutions to constraint satisfaction problems

We show that computing the log-partition function (free-energy) of conditioned inhomogeneous Curie--Weiss spin Hamiltonians reduces to an unbalanced

2 \to 1

norm computation, and design a polynomial-time SDP algorithm for this problem with a lower bound proof for the amount of unbalance achieved. Applied to the protein Ubiquitin, the framework starts from a known crystal structure, explores alternative backbone conformations across the free-energy landscape, and identifies flexible regions of the protein while preserving its native secondary structure.

Pratik Worah, Subhash Khot, Srinivasa Varadhan

Free Energy Calculation Semidefinite Programming Constraint Satisfaction

May 29, 2026stat.ML

Free energy Estimation on Any State Space

Free energy estimation is a fundamental yet challenging problem, from physics to statistics. Classical approaches rely on thermodynamic transformations, ranging from direct estimation, quasistatic integration, to finite-time averaging. Recent work [He and Du et al., 2025] learns neural transports to significantly accelerate the efficiency in the finite-time regime. In this paper, we generalize this framework to arbitrary state spaces. Building on this view, we develop a generalized neural transport learning approach for efficient estimation. Experiments validate the effectiveness and efficiency of the proposed method beyond continuous settings, extending to discrete and multimodal spaces as well as autoregressive settings. Beyond free energy estimation, we establish algebraic identities and reveal a group-theoretic structure linking infinitesimal time reversal and generalized Doob's

h

-transforms, showing that their compositions form a generalized dihedral group.

Jiajun He, Zijing Ou, Francisco Vargas +4

University of Cambridge · Imperial College London · Xaira Therapeutics +1

Free Energy Calculation Doob H-Transform

May 20, 2026cond-mat.stat-mech

MetaDNS: Enhancing Exploration in Discrete Neural Samplers via Well-Tempered Metadynamics

Sampling from discrete distributions with multiple modes and energy barriers is fundamental to machine learning and computational physics. Recent discrete neural samplers like MDNS suffer from mode collapse and fail to sample high-energy barrier regions between modes, which is critical for free energy estimation and understanding phase transitions. We propose Metadynamics Discrete Neural Sampler (MetaDNS), a general framework integrating well-tempered metadynamics into discrete diffusion or autoregressive samplers. By maintaining an adaptive, history-dependent bias potential along selected low-dimensional coordinates, MetaDNS forces exploration of previously inaccessible regions, enabling free energy reconstruction infeasible with standard neural samplers due to a lack of high-energy samples. On challenging low-temperature benchmarks including Ising, Potts, and the copper-gold binary alloy, MetaDNS reproduces the thermodynamic distribution. Compared to MCMC-based metadynamics, MetaDNS also achieves comparable exploration requiring fewer bias deposition steps.

Xiaochen Du, Juno Nam, Jaemoo Choi +7

Massachusetts Institute of Technology · Georgia Institute of Technology

Free Energy Calculation Adaptive Sampling

May 15, 2026physics.chem-ph

Reweighting free energy profiles between universal machine learning interatomic potentials for fast consensus building

Free energy profiles serve as a fundamental bridge between microscopic atomic fluctuations and macroscopic thermodynamic observables. Estimating the free energy profile along a reaction coordinate, referred to as the potential of mean force (PMF), with density functional theory (DFT) accuracy is computationally expensive. Universal machine learning interatomic potentials (MLIPs) drastically reduce this cost, but their accuracy is strongly determined by their training data and hence can be uncertain for a given system. In this work, we present a systematic and scalable framework for reweighting PMFs, initially sampled with a single 'source' MLIP, across a representative suite of target MLIPs. Because traditional direct exponential reweighting fails for large system sizes due to low phase-space overlap between potentials, we deploy robust analytical corrections. Applying this to a complex 601-atom system of Li

^+

transport in a nanoconfined electrolyte, we demonstrate that a mean energy-gap approximation effectively bypasses statistical collapse, producing a highly stable PMF matching the target PMF. Using this approach, we recover high-fidelity target thermodynamics across multiple DFT reference levels (PBE+D3, PBE-sol, r

^2

SCAN,r

^2

SCAN-D4) at a fraction of the computational cost of full simulations. Furthermore, thermodynamic analysis reveals that the studied MLIPs partition into two distinct clusters driven by their training data. Our reweighting framework successfully recovers target thermodynamic properties--specifically, reaction and activation free energies--even when the phase-space overlap between potentials is critically low. Ultimately, this approach establishes a vital diagnostic protocol to achieve affordable cross-model consensus on materials chemistry properties without redundant, resource-intensive simulations.

Sauradeep Majumdar, Miguel Steiner, Johannes C. B. Dietschreit +4

Department of Material Science and Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, 02139, United States. · Institute of Theoretical Chemistry, University of Vienna, Währinger Str. 17, 1090, Vienna, Austria. · Department of Physical and Macromolecular Chemistry, Charles University, Hlavova 8, Praha 2, 12800, Czech Republic.

Free Energy Calculation Machine Learning Interatomic Potentials Importance Sampling Computational Materials Science

May 4, 2026cs.LG

CARD: Coarse-to-fine Autoregressive Modeling with Radix-based Decomposition for Transferable Free Energy Estimation

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.

Ziyang Yu, Yi He, Wenbing Huang +2

ByteDance Seed · Department of Computer Science and Technology, Tsinghua University · Institute for AI Industry Research (AIR), Tsinghua University +2

Free Energy Calculation Autoregressive Generation

May 1, 2026cs.LG

Free Energy Surface Sampling via Reduced Flow Matching

Sampling the free energy surface, namely, the distribution of collective variables (CVs), is a crucial problem in statistical physics, as it underpins a better understanding of chemical reactions and conformational transitions. Traditional methods for free energy surface sampling involve simulation in high-dimensional configuration space and projecting the resulting configurations onto the CV space. To reduce the computational costs of such sampling, we propose FES-FM, a reduced flow matching (FM) method for free energy sampling (FES). We train a dynamical transport map in the CV space, thereby enabling direct sampling of the free energy surface. For many-particle systems, we construct a prior distribution based on the Hessian at a local minimum of the potential, which ensures both rotation-translation invariance and physically meaningful configurations. We evaluate the proposed method across a variety of potential functions and collective variables. Comparative experiments demonstrate that our approach drastically reduces computational costs while delivering superior accuracy per unit sampling time.

Zichen Liu, Tiejun Li

Center for Data Science, Peking University · LMAM and School of Mathematical Sciences, Peking University · Center for Machine Learning Research, Peking University

Free Energy Calculation Flow Matching Molecular Dynamics Simulation

Mar 27, 2026cs.LG

Curvature-aware Expected Free Energy as an Acquisition Function for Bayesian Optimization

We propose an Expected Free Energy-based acquisition function for Bayesian optimization to solve the joint learning and optimization problem, i.e., optimize and learn the underlying function simultaneously. We show that, under specific assumptions, Expected Free Energy reduces to Upper Confidence Bound, Lower Confidence Bound, and Expected Information Gain. We prove that Expected Free Energy has unbiased convergence guarantees for concave functions. Using the results from these derivations, we introduce a curvature-aware update law for Expected Free Energy and show its proof of concept using a system identification problem on a Van der Pol oscillator. On a two-dimensional benchmark with an oscillatory landscape, our adaptive Expected Free Energy acquisition achieves competitive performance in both regret and mean squared error, unlike the typical acquisition functions that perform well in only one metric.

Ajith Anil Meera, Wouter Kouw

Faculty of Electrical Engineering, TU Eindhoven, The Netherlands

Free Energy Calculation Bayesian Optimization Bayesian Experimental Design

Feb 18, 2026stat.ML

Enhanced Diffusion Sampling: Efficient Rare Event Sampling and Free Energy Calculation with Diffusion Models

The rare-event sampling problem has long been the central limiting factor in molecular dynamics (MD), especially in biomolecular simulation. Recently, diffusion models such as BioEmu have emerged as powerful equilibrium samplers that generate independent samples from complex molecular distributions, eliminating the cost of sampling rare transition events. However, a sampling problem remains when computing observables that rely on states which are rare in equilibrium, for example folding free energies. Here, we introduce enhanced diffusion sampling, enabling efficient exploration of rare-event regions while preserving unbiased thermodynamic estimators. The key idea is to perform quantitatively accurate steering protocols to generate biased ensembles and subsequently recover equilibrium statistics via exact reweighting. We instantiate our framework in three algorithms: UmbrellaDiff (umbrella sampling with diffusion models), MetaDiff (a batchwise analogue for metadynamics), and

Δ

G-Diff (free-energy differences via tilted ensembles). Across toy systems, protein folding landscapes and folding free energies, our methods achieve fast, accurate, and scalable estimation of equilibrium properties within GPU-minutes to hours per system-closing the rare-event sampling gap that remained after the advent of diffusion-model equilibrium samplers.

Yu Xie, Ludwig Winkler, Lixin Sun +10

Microsoft Research AI for Science

Free Energy Calculation Diffusion Sampling Molecular Dynamics Simulation Rare-Event Estimation