PSICalc: a novel approach to identifying and ranking critical non-proximal interdependencies within the overall protein structure.

Motivation: AlphaFold has been a major advance in predicting protein structure, but still leaves the problem of determining which sub-molecular components of a protein are essential for it to carry out its function within the cell. Direct coupling analysis predicts two- and three-amino acid contacts, but there may be essential interdependencies that are not proximal within the 3D structure. The problem to be addressed is to design a computational method that locates and ranks essential non-proximal interdependencies within a protein involving five or more amino acids, using large, multiple sequence alignments (MSAs) for both globular and intrinsically unstructured proteins.