Unraveling the role of physicochemical differences in predicting protein-protein interactions

The ability to accurately predict protein-protein interactions is critically important for understanding major cellular processes. However, current experimental and computational approaches for identifying them are technically very challenging and still have limited success. We propose a new computational method for predicting protein-protein interactions using only primary sequence information. It utilizes the concept of physicochemical similarity to determine which interactions will most likely occur. In our approach, the physicochemical features of proteins are extracted using bioinformatics tools for different organisms. Then they are utilized in a machine-learning method to identify successful protein-protein interactions via correlation analysis. It was found that the most important property that correlates most with the protein-protein interactions for all studied organisms is dipeptide amino acid composition (the frequency of specific amino acid pairs in a protein sequence). While current approaches often overlook the specificity of protein-protein interactions with different organisms, our method yields context-specific features that determine protein-protein interactions. The analysis is specifically applied to the bacterial two-component system that includes histidine kinase and transcriptional response regulators, as well as to the barnase-barstar complex, demonstrating the method's versatility across different biological systems. Our approach can be applied to predict protein-protein interactions in any biological system, providing an important tool for investigating complex biological processes' mechanisms.