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。一项关于盐对侧链相互作用的影响的研究正在出版中（物理化学杂志B）。 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。一个讨论同源建模问题的特邀章节将在未来几个月内出现。一份讨论蛋白质表面侧链构象预测的论文也在准备中。蛋白质-配体相互作用建模所面临的挑战在一本书的章节中进行了讨论（Humana Press，2005）。 与NICHD合作，我们建立了RNA酶H1与RNA-DNA杂合体相互作用的模型（Nucl. Acids Res.，2005年）。与NCI合作，我们正在研究激酶与Hsp 90结合所涉及的相互作用（Nat. Struct. Mol.生物学：2005年，以及正在编写的手稿）。其他几个涉及使用同源模型来指导和解释实验的项目正在进行中。 我们继续致力于设计有效的HSP 90抑制剂，并已开始研究阿片受体的配体。与NIMH的同事合作，进行了量子化学计算，以寻找大脑中受体的更有效和选择性的正电子发射断层扫描（PET）配体（手稿正在准备中）。 与NIDDK合作，我们正在表征碳纳米管的化学，热力学和光谱特性及其与水的相互作用。手稿正在准备中。 我们的Langevin模拟聚脯氨酸肽在隐式溶剂中是必不可少的定量解释的FRET测量进行NIDDK的同事（Proc.Natl. Acad. Sci. USA，2005）。模拟显示肽比预期的更灵活。考虑到模拟动力学导致更好地描述所测得的FRET效率比可以得到一个简单的刚性杆模型的聚脯氨酸。 正在进行A-β淀粉样蛋白探针的分子建模研究，以建立结构-活性关系。还进行了量子化学计算，以量化丙二醇和水分子之间的相互作用能。

We have continued to develop, implement, and apply simulation methods in computational studies of the energetics and dynamics of biomolecular systems. A study of salt effects on side-chain interactions is in press (J. Phys. Chem. B). We also model proteins based on homology and work to improve the generation and refinement of such models. An invited book chapter discussing homology-modeling issues should appear in the coming months. A paper discussing the prediction of side-chain conformations on protein surfaces is also in preparation. The challenges faced in modeling protein-ligand interactions were discussed in a book chapter (Humana Press, 2005). In collaboration with NICHD we built a model of RNase H1 interacting with an RNA-DNA hybrid (Nucl. Acids Res., 2005). In collaboration with NCI we are studying the interactions involved in kinase binding to Hsp90 (Nat. Struct. Mol. Biol., 2005, as well as a manuscript in preparation). Severeral other projects that involve the use of homology models to guide and interpret experiments are underway. We continue to work on the design of potent HSP90 inhibitors and have begun studying ligands for opioid receptors. In collaboration with NIMH colleagues, quantum chemical calculations were done in search of more potent and selective positron emission tomography (PET) ligands for receptors in the brain (manuscript in preparation). In collaboration with NIDDK, we are characterizing the chemistry, thermodynamics, and spectroscopic properties of carbon nanotubes and their interactions with water. A manuscript is in preparation. Our Langevin simulations of poly-proline peptides in an implicit solvent were essential for the quantitative interpretation of FRET measuments performed by NIDDK colleagues (Proc. Natl. Acad. Sci. USA, 2005). The simulations showed the peptides to be more flexible than expected. Taking the simulated dynamics into account led to a much better description of the measured FRET efficiencies than could be obtained with a simple rigid-rod model of poly-proline. Molecular modeling studies on the A-beta amyloid probes are being carried out to establish a structure-activity relationship. Quantum chemical calculations are also being carried out to quantify the interaction energy between propanediol and water molecules.