PILOT: Deep Siamese network with hybrid attention improves prediction of mutation impact on protein stability

Evaluating the mutation impact on protein stability (ΔΔG) is essential in the study of protein engineering and understanding molecular mechanisms of disease-associated mutations. Here, we propose a novel deep learning framework, PILOT, for improved prediction of ΔΔG using a Siamese network with hybrid attention mechanism. The PILOT framework leverages multiple attention modules to effectively extract representations for amino acids, atoms, and protein sequences, respectively. This approach significantly ensures the deep fusion of structural information at both residue and atom levels, the seamless integration of structural and sequence representations, and the effective capture of both long-range and short-range dependencies among amino acids. Our extensive evaluations demonstrate that PILOT greatly outperforms other state-of-the-art methods. We also showcase that PILOT identifies exceptional patterns for different mutation types. Moreover, we illustrate the clinical applicability of PILOT in highlighting pathogenic variants from benign variants and VUS (variants of uncertain significance), and distinguishing de novo mutations in disease cases and controls. In summary, PILOT presents a robust deep learning tool that could offer significant insights into drug design, medical applications, and protein engineering studies.