Majdi Hassan

Leon Klein

Saifuddin Syed

Michael M. Bronstein

Alexander Tong

Efficient equilibrium sampling of molecular conformations remains a core challenge in computational chemistry and statistical inference. Cla… (voir plus)ssical approaches such as molecular dynamics or Markov chain Monte Carlo inherently lack amortization; the computational cost of sampling must be paid in-full for each system of interest. The widespread success of generative models has inspired interest into overcoming this limitation through learning sampling algorithms. Despite performing on par with conventional methods when trained on a single system, learned samplers have so far demonstrated limited ability to transfer across systems. We prove that deep learning enables the design of scalable and transferable samplers by introducing Prose, a 280 million parameter all-atom transferable normalizing flow trained on a corpus of peptide molecular dynamics trajectories up to 8 residues in length. Prose draws zero-shot uncorrelated proposal samples for arbitrary peptide systems, achieving the previously intractable transferability across sequence length, whilst retaining the efficient likelihood evaluation of normalizing flows. Through extensive empirical evaluation we demonstrate the efficacy of Prose as a proposal for a variety of sampling algorithms, finding a simple importance sampling-based finetuning procedure to achieve superior performance to established methods such as sequential Monte Carlo on unseen tetrapeptides. We open-source the Prose codebase, model weights, and training dataset, to further stimulate research into amortized sampling methods and finetuning objectives.

2025-08-25

ArXiv (prépublication)

arxiv.org

Amortized Sampling with Transferable Normalizing Flows

Charlie B. Tan

Leon Klein

Saifuddin Syed

Michael M. Bronstein

Alexander Tong

Efficient equilibrium sampling of molecular conformations remains a core challenge in computational chemistry and statistical inference. Cla… (voir plus)ssical approaches such as molecular dynamics or Markov chain Monte Carlo inherently lack amortization; the computational cost of sampling must be paid in-full for each system of interest. The widespread success of generative models has inspired interest into overcoming this limitation through learning sampling algorithms. Despite performing on par with conventional methods when trained on a single system, learned samplers have so far demonstrated limited ability to transfer across systems. We prove that deep learning enables the design of scalable and transferable samplers by introducing Prose, a 280 million parameter all-atom transferable normalizing flow trained on a corpus of peptide molecular dynamics trajectories up to 8 residues in length. Prose draws zero-shot uncorrelated proposal samples for arbitrary peptide systems, achieving the previously intractable transferability across sequence length, whilst retaining the efficient likelihood evaluation of normalizing flows. Through extensive empirical evaluation we demonstrate the efficacy of Prose as a proposal for a variety of sampling algorithms, finding a simple importance sampling-based finetuning procedure to achieve superior performance to established methods such as sequential Monte Carlo on unseen tetrapeptides. We open-source the Prose codebase, model weights, and training dataset, to further stimulate research into amortized sampling methods and finetuning objectives.

2025-08-01

arXiv (publié)

Amortized Sampling with Transferable Normalizing Flows

Charlie B. Tan

Leon Klein

Saifuddin Syed

Michael M. Bronstein

Alexander Tong

2025-06-11

ICML.cc/2025/Workshop/GenBio (spotlight)

openreview.net

Self-Refining Training for Amortized Density Functional Theory

Cristian Gabellini

Hatem Helal

Density Functional Theory (DFT) allows for predicting all the chemical and physical properties of molecular systems from first principles by… (voir plus) finding an approximate solution to the many-body Schr\"odinger equation. However, the cost of these predictions becomes infeasible when increasing the scale of the energy evaluations, e.g., when calculating the ground-state energy for simulating molecular dynamics. Recent works have demonstrated that, for substantially large datasets of molecular conformations, Deep Learning-based models can predict the outputs of the classical DFT solvers by amortizing the corresponding optimization problems. In this paper, we propose a novel method that reduces the dependency of amortized DFT solvers on large pre-collected datasets by introducing a self-refining training strategy. Namely, we propose an efficient method that simultaneously trains a deep-learning model to predict the DFT outputs and samples molecular conformations that are used as training data for the model. We derive our method as a minimization of the variational upper bound on the KL-divergence measuring the discrepancy between the generated samples and the target Boltzmann distribution defined by the ground state energy. To demonstrate the utility of the proposed scheme, we perform an extensive empirical study comparing it with the models trained on the pre-collected datasets. Finally, we open-source our implementation of the proposed algorithm, optimized with asynchronous training and sampling stages, which enables simultaneous sampling and training. Code is available at https://github.com/majhas/self-refining-dft.

2025-06-02

ArXiv (prépublication)

arxiv.org

Self-Refining Training for Amortized Density Functional Theory

Cristian Gabellini

Hatem Helal

Density Functional Theory (DFT) allows for predicting all the chemical and physical properties of molecular systems from first principles by… (voir plus) finding an approximate solution to the many-body Schrödinger equation. However, the cost of these predictions becomes infeasible when increasing the scale of the energy evaluations, e.g., when calculating the ground-state energy for simulating molecular dynamics. Recent works have demonstrated that, for substantially large datasets of molecular conformations, Deep Learning-based models can predict the outputs of the classical DFT solvers by amortizing the corresponding optimization problems. In this paper, we propose a novel method that reduces the dependency of amortized DFT solvers on large pre-collected datasets by introducing a self-refining training strategy. Namely, we propose an efficient method that simultaneously trains a deep-learning model to predict the DFT outputs and samples molecular conformations that are used as training data for the model. We derive our method as a minimization of the variational upper bound on the KL-divergence measuring the discrepancy between the generated samples and the target Boltzmann distribution defined by the ground state energy. To demonstrate the utility of the proposed scheme, we perform an extensive empirical study comparing it with the models trained on the pre-collected datasets. Finally, we open-source our implementation of the proposed algorithm, optimized with asynchronous training and sampling stages, which enables simultaneous sampling and training. Code is available at https://github.com/majhas/self-refining-dft.

2025-06-01

arXiv (publié)

arxiv.org

ET-Flow: Equivariant Flow-Matching for Molecular Conformer Generation

Nikhil Shenoy

Jungyoon Lee

Hannes Stärk

Stephan Thaler