A Practical Covariance-Based Method for Efficient Detection of Protein-Protein Attractive and Repulsive Interactions in Molecular Dynamics Simulations

Molecular dynamics of large protein–protein complexes requires scalable analysis. We present a correlation-based workflow that systematically identifies stabilizing salt bridges, hydrogen bonds, hydrophobic contacts, and destabilizing repulsive interactions across extensive interfaces. By constructing an inter-protein covariance matrix, filtering residue pairs based on distance, and identifying interactions underlying these correlations, our method focuses computational resources on the most relevant regions of the interface while preserving a high level of detail.