PackFlow: Generative Molecular Crystal Structure Prediction via Reinforcement Learning Alignment

TL;DR

PackFlow is a novel reinforcement learning framework for molecular crystal structure prediction that generates physically plausible crystal proposals, improving candidate quality and energy ranking in CSP pipelines.

Contribution

Introducing PackFlow, a flow matching approach with physics alignment reinforcement learning to enhance molecular crystal structure prediction accuracy.

Findings

Outperforms heuristic methods in generating structurally similar proposals.

Produces candidates that relax into lower-energy minima.

Enhances CSP workflows by focusing probability on low-energy structures.

Abstract

Organic molecular crystals underpin technologies ranging from pharmaceuticals to organic electronics, yet predicting solid-state packing of molecules remains challenging because candidate generation is combinatorial and stability is only resolved after costly energy evaluations. Here we introduce PackFlow, a flow matching framework for molecular crystal structure prediction (CSP) that generates heavy-atom crystal proposals by jointly sampling Cartesian coordinates and unit-cell lattice parameters given a molecular graph. This lattice-aware generation interfaces directly with downstream relaxation and lattice-energy ranking, positioning PackFlow as a scalable proposal engine within standard CSP pipelines. To explicitly steer generation toward physically favourable regions, we propose physics alignment, a reinforcement learning post-training stage that uses machine-learned interatomic potential energies and forces as stability proxies. Physics alignment improves physical validity without altering inference-time sampling. We validate PackFlow's performance against heuristic baselines through two distinct evaluations. First, on a broad unseen set of molecular systems, we demonstrate superior candidate generation capability, with proposals exhibiting greater structural similarity to experimental polymorphs. Second, we assess the full end-to-end workflow on two unseen CSP blind-test case studies, including relaxation and lattice-energy analysis. In both settings, PackFlow outperforms heuristics-based methods by concentrating probability mass in low-energy basins, yielding candidates that relax into lower-energy minima and offering a practical route to amortize the relax-and-rank bottleneck.