PepTri: Tri-Guided All-Atom Diffusion for Peptide Design via Physics, Evolution, and Mutual Information

Abstract

Peptides, short chains of amino acids capable of high-specificity protein binding, represent a powerful class of therapeutics. While deep generative models have shown promise for peptide design, existing approaches are often structure-centric and therefore generate sequences and structures in a decoupled manner, failing to ensure that designs are simultaneously physically stable, evolutionarily plausible, and internally coherent. To overcome this limitation, we introduce $PepTri$, a novel diffusion framework that addresses this by jointly generating peptide sequences and 3D structures within a unified, $SE(3)$-equivariant latent space. Our proposed model integrates three complementary guidance signals during the generative process: (i) physics-informed guidance via differentiable molecular mechanics to ensure structural stability and realism; (ii) evolutionary guidance to bias sequences toward conserved, functional motifs; and (iii) mutual information guidance to explicitly maximize sequence-structure coherence. This tri-guided approach ensures the generative process is steered by biophysical laws, biological priors, and information-theoretic alignment in tandem. Extensive evaluations on challenging peptide-protein design benchmarks, cross-domain (PepBench, LNR) and in-domain (PepBDB), demonstrate that PepTri substantially outperforms strong baselines, achieving state-of-the-art results in binding affinity, structural accuracy, and design diversity. Our results establish that integrating these complementary signals directly into the denoising process is crucial for generating viable, high-quality peptide medicines. PepTri is available at: https://github.com/aigensciences/PepTri