Let Physics Guide Your Protein Flows: Topology-aware Unfolding and Generation
This addresses the need for physically realistic protein generation for computational biology, though it appears incremental as it builds on existing flow-matching paradigms.
The authors tackled the problem of diffusion-based protein generation lacking physical realism by introducing a physics-guided noising process that preserves topological integrity, achieving state-of-the-art performance in unconditional protein generation with more designable and novel structures.
Protein structure prediction and folding are fundamental to understanding biology, with recent deep learning advances reshaping the field. Diffusion-based generative models have revolutionized protein design, enabling the creation of novel proteins. However, these methods often neglect the intrinsic physical realism of proteins, driven by noising dynamics that lack grounding in physical principles. To address this, we first introduce a physically motivated non-linear noising process, grounded in classical physics, that unfolds proteins into secondary structures (e.g., alpha helices, linear beta sheets) while preserving topological integrity--maintaining bonds, and preventing collisions. We then integrate this process with the flow-matching paradigm on SE(3) to model the invariant distribution of protein backbones with high fidelity, incorporating sequence information to enable sequence-conditioned folding and expand the generative capabilities of our model. Experimental results demonstrate that the proposed method achieves state-of-the-art performance in unconditional protein generation, producing more designable and novel protein structures while accurately folding monomer sequences into precise protein conformations.