Simulating Protein Structures, Complexes, And Dynamics

我们继续发展，实施和应用模拟方法在生物分子系统的能量学和动力学的计算研究。 我们正在努力完善一个连续描述的极性，非极性和溶剂结构的影响方面的大分子溶剂化。 详细了解水溶液及其对生物分子的影响，应加快未来的改进，连续描述，并已发表两篇论文报告原子模拟的离子簇在溶液中（SA哈桑）。 我们还基于同源性对蛋白质进行建模，并致力于改进此类模型的生成和改进。 我们与NICHD一起发表了一项III型磷脂酰肌醇4-激酶抑制剂敏感性的研究（A Balla et al.）。 与OD合作，我们模拟了HIV包膜糖蛋白gp 120的缺失突变体，其中CD 4结合位点的暴露导致两种单克隆抗体的结合增强。 该研究发表在Virology（I Berkower et al.）上。 其他建模研究的gp 120和委内瑞拉马脑炎（VEE）蛋白酶的初步阶段。 与NCI，我们正在准备一份手稿，其中同源建模用于研究与皮肤病相关的基因突变。 我们与NIMH和NHLBI合作发表了一项研究，描述了确定外周苯二氮卓类受体配体过渡态的可靠方法（YS Lee等人）。 在这项研究的基础上，我们正在应用量子力学计算来理解合成新型PET配体所涉及的机制。 与NIDA，我们正在研究阿片受体配体的结构-活性关系，试图设计和合成新的阿片类镇痛药。 发表了一篇论文（J Zezula等人），一份已提交，第三份正在编写中。 与NCI正在进行的合作研究包括设计和合成一系列新的HSP 90抑制剂。 与NICHD，我们正在研究AANAT的动力学和能量学，第一个酶在降钙素-褪黑激素转化途径，并发表了一篇论文（J Pavlicek等人）。 此外，与NICHD，我们已经提交了一份手稿出版，其中蒙特卡洛和分子动力学模拟用于研究催乳素受体相互作用的结构性质和结合和识别的特异性。 催乳素是一种与人类乳腺肿瘤发展有关的激素。 通过NINDS，我们使用计算机建模来更好地理解细胞周期蛋白依赖性激酶5（cdk 5）功能的结构和动力学基础。 cdk 5的失调可能与神经退行性疾病如阿尔茨海默病有关。 我们也一直致力于开发计算方法，以获得可靠的G蛋白偶联受体（GPCR）的结构。 现实的模型可以用来研究GPCR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. A detailed understanding of aqueous solutions and their effects on biomolecules should expedite future improvements to a continuum description, and two papers have been published reporting atomistic simulations of ion clusters in solution (SA Hassan). We also model proteins based on homology and work to improve the generation and refinement of such models. With NICHD, we have published a study of the inhibitor sensitivities of type-III phosphatidylinositol 4-kinase enzymes (A Balla et al.). 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. This study was published in Virology (I Berkower et al.). Additional modeling studies of gp120 and of Venezuelan equine encephalitis (VEE) protease are in preliminary stages. With NCI, we are preparing a manuscript in which homology modeling is used to investigate genetic mutations associated with skin disease. In collaboration with NIMH and NHLBI, we published a study describing reliable ways of determining the transition state of peripheral benzodiazepine receptor ligands (YS Lee et al.). Building on this study, we are applying quantum mechanical calculations to understand the mechanisms involved in synthesizing novel PET ligands. With NIDA, we are studying the structure-activity relationships of opioid-receptor ligands, in attempts to design and synthesize novel opioid analgesics. One paper was published (J Zezula et al.), one has been submitted, and a third is in preparation. 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, and a paper was published (J Pavlicek et al.). Also with NICHD, we have submitted a manuscript for publication in which Monte Carlo and molecular dynamics simulations were used 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. With NINDS, we are using computer modeling to better understand the structural and dynamical basis for the function of cyclin-dependent kinase 5 (cdk5). The deregulation of cdk5 may be involved in neurodegenerative diseases such as Alzheimer's disease. 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.