DARMN: Domain-Aware Residual Feature Modulation Network for Multidomain Protein Dynamic Inter-Residue Contact Prediction.

Abstract

The regulation of conformational stability in multidomain proteins (MDP) is a central challenge in protein engineering with major implications for antigen optimization, enzyme activity modulation, and signal transduction. The function of these proteins depends on the properties of their constituent domains as well as on interdomain orientation and interface rearrangement during conformational transitions. Previous studies show that conformational transition is largely governed by changes in a small number of key residue pairs. However, such dynamic inter-residue contacts are typically sparse, transient, and coupled to large-scale domain motions, making them difficult to resolve directly by experiments or simulations. Existing deep-learning methods of dynamic contact prediction also lack specialized modeling for multidomain systems. Here, we present the Domain-Aware Residual Feature Modulation Network (DARMN), a deep learning framework for dynamic inter-residue contact prediction in MDP. Built on AlphaFold2 representations, DARMN uses coevolutionary information from multiple sequence alignments to capture sparse interdomain contact signals and applies Residual Feature-wise Linear Modulation to efficiently fuse single and pair representations. Furthermore, we design a domain-aware weighted focal loss function to distinguish between intradomain and interdomain contacts, thereby alleviating class imbalance and enhancing the learning of interdomain contacts. DARMN outperforms existing dynamic contact prediction and conformational ensemble prediction models, especially in long-distance contact identification, and generalizes well to unseen MDP. DARMN thus provides a useful computational framework for sequence design targeting conformational stabilization and mechanistic studies of MDP.