THFlow: A Temporally Hierarchical Flow Matching Framework for 3D Peptide Design
This addresses a key bottleneck in peptide-based therapeutic development by enhancing generative models for more effective drug design, though it is incremental as it builds on flow matching methods.
The paper tackles the multimodal temporal inconsistency problem in 3D peptide design, where early optimization of conformation is ineffective due to lack of interaction, and proposes THFlow, a flow matching framework that models temporal hierarchy to improve binding affinity, outperforming existing methods in stability, affinity, and diversity.
Deep generative models provide a promising approach to de novo 3D peptide design. Most of them jointly model the distributions of peptide's position, orientation, and conformation, attempting to simultaneously converge to the target pocket. However, in the early stage of docking, optimizing conformation-only modalities such as rotation and torsion can be physically meaningless, as the peptide is initialized far from the protein pocket and no interaction field is present. We define this problem as the multimodal temporal inconsistency problem and claim it is a key factor contributing to low binding affinity in generated peptides. To address this challenge, we propose THFlow, a novel flow matching-based multimodal generative model that explicitly models the temporal hierarchy between peptide position and conformation. It employs a polynomial based conditional flow to accelerate positional convergence early on, and later aligns it with rotation and torsion for coordinated conformation refinement under the emerging interaction field. Additionally, we incorporate interaction-related features, such as polarity, to further enhance the model's understanding of peptide-protein binding. Extensive experiments demonstrate that THFlow outperforms existing methods in generating peptides with superior stability, affinity, and diversity, offering an effective and accurate solution for advancing peptide-based therapeutic development.