Molecular dynamics simulations of nuclear thyroid hormone receptor mutants

Abstract

We propose a molecular dynamics simulations study of the thyroid hormone nuclear receptor (TR) and several (25) mutants of the TR-beta isoform in order to investigate the structural and dyamical changes of the mutants with respect to the TR-beta wild type. The mutations we intend to investigate are largely involved in the thyroid hormone resistance syndrome, in an attempt to contribute to the understanding of the molecular basis of this disease. Other mutants we intend to study are associated to the dimerization surface and the region of interaction with coregulator proteins. The main goals of this proposal include:- Analyses of ligand mobility e protein mobility as a whole, the mutated regions more specifically, as well as other regions known to be important to the protein function.- Analyses of ligand-protein interactions and differences induced by the mutations, and ligand-solvent interactions.- Interpretation and correlation of the results obtained from the simulations with biological functional assays of the mutants available in the literature.