Joint Geometric-Chemical Distance for Protein Surfaces

TL;DR

This paper introduces IFACE, a novel framework that aligns protein surfaces by coupling geometric and chemical information, enabling more accurate comparison of protein structures and functional sites.

Contribution

The paper presents a new probabilistic method for aligning protein surfaces that jointly considers shape and chemistry, improving structural comparison accuracy.

Findings

Better separation of conformational variability from structural divergence.

Reveals conserved catalytic pockets in cytochrome P450 family.

Provides a unified distance measure for protein surface comparison.

Abstract

Protein function is executed at the molecular surface, where shape and chemistry act together to govern interaction. Yet most comparison methods treat these aspects separately, privileging either global fold or local descriptors and missing their coupled organization. Here we introduce IFACE (Intrinsic Field-Aligned Coupled Embedding), a correspondence-based framework that aligns protein surfaces through probabilistic coupling of intrinsic geometry with spatially distributed chemical fields. From this alignment, we derive a joint geometric--chemical distance that integrates structural and physicochemical discrepancies within a single formulation. Across diverse proteins, this distance separates conformational variability from true structural divergence more effectively than fold-based similarity measures. Applied to the cytochrome P450 family, it reveals coherent family-level organization and identifies conserved buried catalytic pockets despite the complex topology. By linking interpretable surface correspondences with a unified distance, IFACE establishes a principled basis for comparing protein interfaces and detecting functionally related interaction patches across proteins.