Synergistic Attention-Guided Cascaded Graph Diffusion Model for Complementarity Determining Region Synthesis.

Abstract

Complementarity determining region (CDR) is a specific region in antibody molecules that binds to antigens, where a small portion of residues undergoes particularly pronounced variations. Generating CDRs with high affinity and specificity is a pivotal milestone in accelerating drug development for daunting and unresolved diseases. However, existing approaches predominantly center on characterizing the attributes of residues through sequential generation models, thus falling short in effectively modeling the intricate spatial correlations among residues and frequently succumbing to the trap of generating sequences that exhibit a high degree of arbitrariness. In this article, we propose a novel synergistic attention-guided cascaded graph diffusion model, termed GraphCas, which offers a pathway for optimized generation of high-affinity CDRs. Our approach is the first cascaded-based graph diffusion model for CDR synthesis. Specifically, we design a graph propagation algorithm with a relation-aware synergistic attention mechanism, enabling the targeted acquisition of structural insights from diverse protein sequences and bolstering the global information representation of the graph by precisely localizing to long-range key residue sites. We design a cascaded conditional enhanced diffusion approach, providing the capability to incorporate additional control constraints into the input. Experimental results demonstrate that GraphCas can generate photo-realistic CDRs and achieve performance comparable to top-tier approaches. In particular, GraphCas reduces the RMSD by nearly 0.42 units in the H1 region and improves the ERRAT by 9.36% points in the L1 region.