MOLECULAR DYNAMICS OF THYROID HORMONE RECEPTOR COMPLEXES

University Of California San Francisco, San Francisco CA

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Abstract

The structures of the thyroid hormone receptor (TR) in complex with a thyroid hormone isostere (DIMIT) and the native thyroid hormone (T3) have recently been solved using x-ray crystallography. In collaboration with Robert Fletterick at UCSF, we have begun molecular dynamics (MD) simulations of the TR/DIMIT complex. Our goals in this research are to (1) provide a microscopic understanding of the dynamics of the protein-hormone complex; (2) use free energy derivative or free energy perturbation simulations to understand the energetics of this complex and suggest novel agonists or antagonists of thyroid hormone activity; and (3) make a predictive simulation of the hormone-less aporeceptor starting from the TR/T3 structure. We are using the Computer Graphics Laboratory (CGL) facilities to evaluate our simulations, primarily through the use of the MidasPlus molecular modeling software. In particular, we have evaluated the structure-activity relationships of the TR/T3 complex through free energy estimation techniques and made use of MidasPlus delegates to project our free energy data on structures of the complex. This permits us to rationalize the receptor's preference for different substituents at varying points on the hormone, and also allows prediction of novel ligand structures.