The structure of the thyroid hormone receptor (TR) in complex with a thyroid hormone isostere (DIMIT) was recently solved using x-ray crystallography. This work was carried out by the research group of Robert Fletterick at UCSF. In collaboration with these researchers, 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 true thyroid hormone/TR complex starting from the TR/DIMIT structure. We have used the Computer Graphics Laboratory (CGL) facilities to evaluate our simulations, primarily through the use of the MidasPlus molecular modeling software. In particular, the detailed visualization of individual structures from MD simulations has been invaluable in describing the characteristic motions of the TR/DIMIT complex. The flexible delegate facility of MidasPlus has allowed us to project the motions and fluctuations seen in the simulation onto an average structure of the complex, permitting description of the various motional modes (loop flapping, structural relaxation, isotropic fluctuation).
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