Simulating Protein Structures, Complexes, And Dynamics

我们继续在生物分子系统的能量学和动力学的计算研究中开发、实施和应用模拟方法。我们正致力于根据极性、非极性和溶剂结构效应来完善对大分子溶剂化的连续描述。一份手稿已经出版(J Phys Chem B，2007)，另一份正在准备中。 我们还基于同源性对蛋白质进行建模，并努力改进此类模型的生成和精炼。通过NICHD，我们一直在研究III型磷脂酰肌醇4-激酶酶的抑制剂敏感性，并提交了一份手稿。与OD合作，我们模拟了HIV包膜糖蛋白gp120的一个缺失突变体，该突变体的CD4结合位点的暴露导致两个单抗的结合增强。这项研究提交了一份手稿。 与NIMH和NHLBI合作，我们即将提交一份手稿，描述确定用作脑成像探针的外周苯二氮卓类受体配体过渡状态的可靠方法。在NIDA的帮助下，我们正在研究阿片受体配体的构效关系。一篇论文已经发表(J Med Chem，2007)，另一篇几乎竞争激烈。 与NCI正在进行的合作研究包括设计和合成一系列新的HSP90抑制剂。 通过NICHD，我们正在研究AANAT的动力学和能量学，AANAT是5-羟色胺-褪黑素转化途径中的第一种酶。同样在NICHD，我们一直在使用蒙特卡罗和分子动力学模拟来研究催乳素-受体相互作用的结构性质以及结合和识别的特异性。催乳素是一种荷尔蒙，与人类乳腺肿瘤的发展有关。 我们还一直致力于开发计算方法，以获得可靠的G蛋白偶联受体(GPCRs)结构。真实的模型可以用来研究GPCRs与细胞外和细胞内信号分子的相互作用。

We have continued to develop, implement, and apply simulation methods in computational studies of the energetics and dynamics of biomolecular systems. We are working to refine a continuum description of macromolecular solvation in terms of polar, nonpolar, and solvent-structure effects. One manuscript has been published (J Phys Chem B, 2007), and another is in preparation. We also model proteins based on homology and work to improve the generation and refinement of such models. With NICHD, we have been studying the inhibitor sensitivities of type-III phosphatidylinositol 4-kinase enzymes, and a manuscript has been submitted. Collaborating with OD, we modeled a deletion mutant of the HIV envelope glycoprotein gp120 for which exposure of the CD4 binding site leads to enhanced binding of two monoclonal antibodies. A manuscript was submitted for this study. In collaboration with NIMH and NHLBI, we are about to submit a manuscript describing reliable ways of determining the transition state of peripheral benzodiazepine receptor ligands that are utilized as probes for brain imaging. With NIDA, we are studying the structure-activity relationships of opioid-receptor ligands. One paper has been published (J Med Chem, 2007), and another is nearly competed. Ongoing collaborative research with NCI includes the design and synthesis of a new series of HSP90 inhibitors. With NICHD, we are studying the dynamics and energetics of AANAT, the first enzyme in the serotonin-melatonin conversion pathway. Also with NICHD, we have been using Monte Carlo and molecular dynamics simulations to study the structural nature of prolactin-receptor interactions and the specificity of binding and recognition. Prolactin is a hormone that has been implicated in the development of human breast tumors. We have also been working to develop computational methods for obtaining reliable structures of G protein coupled receptors (GPCRs). Realistic models could be used to investigate the interactions of GPCRs with extracellular and intracellular signaling molecules.