Effect of Lithium Drug on Binding Affinities of Glycogen Synthase Kinase-3 β to Its Network Partners: A New Computational Approach.

Abstract

Finding new methods to study the effect of small molecules on protein interaction networks provides us with invaluable tools in the fields of pharmacodynamics and drug design. Lithium is an antimanic drug that has been used for the treatment of bipolar disorder for more than 60 years. Here, we utilized a new approach to study the effect of lithium as a drug on the protein interaction network of GSK-3β as a hub protein and computed the affinities of GSK-3β to its partners in the presence of lithium or sodium ions. For this purpose, ensembles of GSK-3β protein structures were created in the presence of either lithium or sodium ions using adaptive tempering molecular dynamics simulations. The protein binding patches of GSK-3β for its partners were determined, and finally, the affinity of each binding patch to the related partner was computed for structures of ensembles using a monomer-based approach. Besides, by comparing structural dynamics of GSK-3β during MD simulations in the presence of LiCl and NaCl, we suggested a new mechanism for the inhibitory effect of lithium on GSK-3β.