MOLECULAR DYNAMICS OF THYROID HORMONE RECEPTOR COMPLEXES

甲状腺激素受体复合物的分子动力学

• 批准号: 6456721
• 负责人: JED PITERA
• 金额: $ 27.32万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-07-01 至 2003-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6456721
• 关键词: AIDS; biological products; biomaterials; biomedical resource; immunology; infection; inflammation; lymphatic system; virus

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.

甲状腺激素受体（TR）的结构 甲状腺激素ISOSTOSTERE（DIMIT）和天然甲状腺激素 （T3）最近使用X射线晶体学解决了。 在 与UCSF的Robert Fletterick合作，我们已经开始分子 TR/DIMIT复合物的动力学（MD）模拟。 我们的目标 研究是（1）对 蛋白质激素复合物的动力学； （2）使用自由能 衍生或自由能扰动模拟以了解 这种复合物的能量学并建议新颖的激动剂或拮抗剂 甲状腺激素活性； （3）对 从TR/T3结构开始的无激素的无痛受体。 我们 正在使用计算机图形实验室（CGL）设施 主要通过使用MIDASPLUS评估我们的模拟 分子建模软件。 特别是，我们评估了 TR/T3复合物通过自由的结构活性关系 能源估计技术并利用Midasplus代表到 将我们的自由能数据投射到综合体的结构上。 这 允许我们合理化受体对不同的偏好 激素上不同点的取代基，也允许 新型配体结构的预测。