Entropy Transfer and allosteric Communication in Proteins

The importance of dynamic effects of allosteric drug design are now being recognized. Allosteric communication derives from the propagation of effects between distant points in a protein and is closely related to transfer of entropy between these points. In this communication, two methods of evaluating entropy transfer between residues are presented.The first method isbased on extensive molecular dynamics simulations and the second, a fast and approximate one, based on the coarse-grained Gaussian Network Model of proteins. In this brief communication, we discuss two examples, one each of these two methods and determine the extent of entropic coupling between residues resulting from binding of a substrate. Predictions of both models on allosteric communication patterns show that transfer of information in proteins does not necessarily follow a single path, but involves essentially the full protein. It is also shown that considering entropy only is not sufficient to detect allosteric communication and additional information based on time delayed correlations should be introduced. We show that binding of a substrate to the protein introduces new inter-residue correlations to the protein and changes the entropy transfer features of residues. The decrease in the entropy or the level of uncertainty in the fluctuations of residues upon binding is expected to be of great importance for allosteric drug design.The two models that we discuss are (i) ubiquitin and its complex with a substrate, and (ii) the PDZ domain and its behavior in the presence and absence of its C-terminal tail.