Relationships between ligand binding sites, protein architecture and correlated paths of energy and conformational fluctuations

Abstract

Statistical thermodynamics basis of energy and residue position fluctuations is explained for native proteins. The protein and its surroundings are treated as a canonical system with emphasis on the effects of energy exchange between the two. Fluctuations of the energy are related to fluctuations of residue positions, which in turn are related to the connectivity matrix of the protein, thus establishing a connection between energy fluctuation pathways and protein architecture. The model gives the locations of hotspots for ligand binding, and identifies the pathways of energy conduction within the protein. Results are discussed in terms of two sets of models, the BPTI and twelve proteins that contain the PDZ domain. Possible use of the model for determining functionally similar domains in a diverse set of proteins is pointed out.