Simulating Protein Structures, Complexes, And Dynamics

我们继续在生物分子系统的能量学、动力学和机制的计算研究中开发、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。对水溶液及其对生物分子的影响的详细了解将加快未来对连续描述的改进，并已出版了应邀出版的一本书的章节(Hassan和Mehler)。 我们还利用从头算量子化学方法研究了生物活性化合物在基态和过渡态的几何构型和能级。这种方法在阐明无法通过实验探测的感兴趣的化学反应(例如，二芳基碘18F-氟化物)的过渡态时特别有用。由此得到的过渡态信息为通过化学修饰调节反应的产物选择性提供了洞察力。 我们还一直致力于开发应用于多肽、蛋白质-蛋白质复合体和G蛋白偶联受体(GPCRs)的结构预测方法。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。 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。已经为内部同事建立了几个初步模型，并预计会有相关的手稿。 我们与NIMH和NHLBI合作，进行了从头算量子化学计算，在原子水平上阐明了二芳基碘盐的氟化机理。对这一过程的理解对于开发用于脑成像的新型18F标记PET探针至关重要。在这一努力中，我们将放射性氟化产物的选择性与两个相应过渡态的激活自由能的差异联系起来(Chun等人)。此外，基于计算的二聚体2-甲氧基苯基(2-甲氧基苯基)氯化碘的稳定性，我们提出了二芳基碘卤化物与18F离子的反应需要二聚体解离成单体，以便用18F离子取代氯离子(Lee等人)。另外两份与机制有关的文件正在编写中。 在NIDA/NIAAA的基础上，我们提出了阿片受体配体的构效关系，试图设计和合成新型的阿片类止痛药。发表了两篇论文，并提交了另一份手稿。特别是，2009年的论文(Zhang等人)发表在百年纪念的《药物化学杂志》上。 利用NIAID，我们正在研究硝基咪唑的还原机理。这项研究利用量子力学和分子力学的组合潜力，追求设计更好的结核病药物。 在NICHD，我们发表了一篇论文，其中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(谢等人)。催乳素是一种荷尔蒙，与人类乳腺肿瘤的发展有关。 在NINDS中，我们使用计算机建模来更好地理解细胞周期蛋白依赖蛋白依赖性激酶5(CDK5)功能的结构和动力学基础。CDK5的失控可能与阿尔茨海默病等神经退行性疾病有关。发表了一篇论文(Cardone等人)。

We have continued to develop, implement, and apply simulation methods in computational studies of the energetics, dynamics, and mechanisms 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 an invited book chapter has been published (Hassan and Mehler). We also utilize ab-initio quantum chemical approach to investigate the geometry and energetics of bioactive compounds in ground and transition states. This approach is particularly useful in elucidating the transition states of chemical reactions of interest (e.g., diaryliodonium 18F-fluoride) that cannot be probed by experiments. The resulting transition-state information provides insight into the modulation of the product selectivity of reactions via chemical modifications. We have also been working to develop structure-prediction methods for application to peptides, protein-protein complexes, and G protein coupled receptors (GPCRs). Realistic models could be used to investigate the interactions of GPCRs with extracellular and intracellular signaling molecules. We also model proteins based on homology and have worked to improve the generation and refinement of such models. Several preliminary models have been built for intramural colleagues, and associated manuscripts are anticipated. In collaboration with NIMH and NHLBI, we have carried out ab-initio quantum chemical calculations to elucidate the fluorination mechanism of diaryliodonium salts at the atomic level. An understanding of this process is essential in the development of novel 18F-labeled PET probes for brain imaging. In this endeavor, we have related the radio-fluorinated product selectivity to the differences in activation free energies of the two respective transition states (Chun et al.). Also, based on the calculated stability of the dimeric 2-methylphenyl(2-methoxyphenyl)iodonium chloride, we have proposed that reactions of diaryliodonim halides with 18F ions require the dissociation of dimers to monomers to allow the replacement of chloride ions with 18F ions (Lee et al.) Two additional mechanism related papers are in preparation. With NIDA/NIAAA, we have proposed the structure-activity relationships of opioid-receptor ligands, in attempts to design and synthesize novel opioid analgesics. Two papers were published and another manuscript has been submitted. In particular, the 2009 paper (Zhang et al.) was published in the centennial issue of the Journal of Medicinal Chemistry. With NIAID, we are investigating the nitroimidazole reduction mechanism. This study utilizes the combined potentials of quantum mechanics and molecular mechanics, in pursuit of designing better drugs for tuberculosis. With NICHD, we published a paper 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 (Xie et al.). Prolactin is a hormone that has been implicated in the development of human breast tumors. With NINDS, we used 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. A paper was published (Cardone et al.).