ConTact: Contact-First Antibody CDR Design via Explicit Interface Reasoning

TL;DR

ConTact is a novel antibody CDR design architecture that explicitly models contact prediction and sequence generation, leading to improved structural and epitope awareness performance.

Contribution

It introduces a contact-then-act framework with explicit contact reasoning and geometric priors, advancing antibody CDR design methods.

Findings

Achieves 7% RMSD improvement over baselines

Improves epitope awareness by 10% F1 score

Maintains competitive sequence recovery (AAR 0.38)

Abstract

Computational antibody CDR design methods condition on antigen structure to generate binding loops, yet existing architectures conflate two fundamentally distinct sub-problems: identifying which CDR positions will contact the antigen, and selecting amino acids at those positions. This conflation forces models to learn contact reasoning implicitly through uniform message passing, diluting antigen signal across all positions equally. We introduce ConTact, a contact-then-act architecture that explicitly decomposes CDR design into three cascaded stages: learning surface complementarity fingerprints, predicting CDR-antigen contacts, and injecting contact-gated antigen features into the sequence head. A distance-biased cross-attention module encodes geometric priors favoring spatial neighbors, while a contact-weighted cross-entropy loss concentrates gradient signal on binding-critical positions. On CHIMERA-Bench dataset, ConTact achieves the best structural quality (7% RMSD improvement over the next-best baseline), best epitope awareness (10% F1 score over GNN baselines), and competitive sequence recovery (AAR 0.38) among several CDR-H3 design baselines.