SurfDesign: Effective Protein Design on Molecular Surfaces
For protein engineers, this provides a more principled approach to functional protein design by leveraging surface geometry, though it is an incremental improvement over existing surface-conditioned methods.
SurfDesign introduces a surface-conditioned protein design framework that models molecular surfaces as continuous geometric manifolds, outperforming prior methods on de novo binder and enzyme design benchmarks.
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 https://github.com/smiles724/SurfDesign.