ConformFlow: scalable normalizing flow for protein conformational ensemble generation

Abstract

AO_SCPLOWBSTRACTC_SCPLOWMolecular dynamics (MD) simulations remain the standard tool for characterizing protein conformational landscapes, but their high computational cost limits large-scale and long-timescale applications. Recent generative models, especially diffusion-based approaches, provide promising alternatives by learning equilibrium conformational distributions across diverse protein systems. We present ConformFlow, the first scalable normalizing-flow framework for sequence-conditioned protein conformational ensemble generation. ConformFlow combines a continuous backbone latent representation with a RealNVP-style flow parameterized by sequence-aware Transformer coupling networks, enabling exact likelihood training, single-step sampling, and plug-and-play conditioning on flexible geometric constraints. Across diverse protein systems, ConformFlow generates ensembles that agree well with reference MD simulations, generalizes to proteins beyond its training data, and achieves substantially faster sampling than diffusion-based baselines. These results establish ConformFlow as an efficient and controllable alternative for protein conformational ensemble generation. Codehttps://github.com/Harrydirk41/ConformFlow.git