Protein inverse folding through joint modeling of surface and backbone geometry

Abstract

Inverse protein folding aims to generate amino acid sequences compatible with a given protein structure. While recent deep learning methods have achieved strong performance by conditioning on residue-level backbone geometry, backbone-only representations insufficiently constrain surface-exposed residues and thus incompletely capture the structural determinants of sequence identity. Here we propose Surleton, a structure-aware inverse folding framework that jointly models backbone geometry and protein surface organization. By integrating complementary surface geometric information, Surleton refines the conditional sequence distribution and improves the balance of sequence modeling across buried and exposed residues. On the CATH4.2 and SCOPe benchmarks, Surleton consistently outperforms backbone-only baselines in sequence recovery, sequence similarity, and predictive confidence, with especially strong improvements on surface-exposed residues. Together, these findings indicate that protein surface geometry serves as a complementary source of structural constraint and that surface-aware modeling may provide a promising direction for improving inverse protein folding.