SurfDesign: Effective Protein Design on Molecular Surfaces

Fang Wu, Shuting Jin, Xiangru Tang, Mark Gerstein, Xiangxiang Zeng, Yejin Choi, Jure Leskovec, Jinbo Xu

Keywords: Protein Design, Surface Modeling

Abstract: Protein function is largely determined by molecular surface geometry and physicochemical complementarity, yet most protein design methods condition only on backbone structure. We introduce SurfDesign, a surface-conditioned protein design framework that models molecular surfaces as continuous geometric manifolds and integrates them with pretrained protein language models. SurfDesign employs surface-based equivariant message passing to capture surface normals, curvature, and directional geometry, together with a parameter-efficient fine-tuning strategy. Focusing on functional protein design, we show that SurfDesign consistently outperforms prior surface-conditioned and backbone-only methods on de novo binder and enzyme design benchmarks. We also report strong performance on inverse-folding benchmarks as a diagnostic of structural compatibility. Our results highlight manifold-aware surface representations as a principled foundation for functional protein and enzyme design. Code is available at~\url{https://github.com/smiles724/SurfDesign}.

Email Sharing: We authorize the sharing of all author emails with Program Chairs.

Data Release: We authorize the release of our submission and author names to the public in the event of acceptance.

Submission Number: 6