Sequence-based coevolutionary prediction of species-specific interactomes

Evolutionarily conserved protein-protein interactions (PPIs) reveal fundamental biological processes. However, predicting protein function solely from these interactions provides an incomplete picture of biological systems. Computational methods for predicting PPIs often struggle due to limited functional annotations in databases, making it difficult to fully understand unique biological systems.. This study introduces ContextMirror2.0 (CM2.0), a coevolution-based method designed to address these limitations. Coevolutionary approaches, unlike supervised machine learning methods, do not rely on labelled datasets, proving valuable in addressing the scarcity of data for species-specific PPIs. While around 40% of CM2.0s top-1000 predicted PPIs for E. coli, S. enterica, and S. aureus are present in experimental PPI databases, a comparative analysis of predicted functional communities revealed highly conserved interaction patterns and species-specific interactions. CM2.0 leverages coevolutionary information to explore protein interaction dynamics and understand the functional consequences of species-specific variations. This information can inform further studies on the emergence of novel functions, adaptation to specific environments, and the development of targeted therapies.