JanusDDG: A Thermodynamics-Compliant Model for Sequence-Based Protein Stability via Two-Fronts Multi-Head Attention

Abstract: Understanding how residue variations affect protein stability is crucial for designing functional proteins and deciphering the molecular mechanisms underlying disease-related mutations. Recent advances in protein LLMs (PLMs) have revolutionized computational protein analysis, enabling, among other things, more accurate predictions of mutational effects. In this work, we introduce JanusDDG, a deep learning framework that leverages PLM-derived embeddings and a bidirectional cross-attention transformer architecture to predict $\Delta \Delta G$ of single and multiple-residue mutations while simultaneously being constrained to respect fundamental thermodynamic properties, such as antisymmetry and transitivity. Unlike conventional self-attention, JanusDDG computes queries (Q) and values (V) as the difference between wild-type and mutant embeddings, while keys (K) alternate between the two. This cross-interleaved attention mechanism enables the model to capture mutation-induced perturbations while preserving essential contextual information. Experimental results show that JanusDDG achieves state-of-the-art performance in predicting $\Delta \Delta G$ from sequence alone, matching or exceeding the accuracy of structure-based methods for both single and multiple mutations. Code Availability:https://github.com/compbiomed-unito/JanusDDG