MOLECULAR DYNAMIC SIMULATION OF THE INTERACTION OF THE ADAPTER WITH THE GENETIC

这个子项目是许多利用 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 本提案中描述的研究是先前由NSF PACI资助的项目的继续，该项目名为“离子通道和受体蛋白的分子模拟”，编号为MCB 040046。在此应用程序中，我们请求支持这个多年奖的第二年（04.01.2008-03.30.2010）和由于我们的研究项目的扩展所需的额外资源。我们建议扩大我们的研究，以包括更多的系统，并测试我们在上一个资助期的工作中提出的假设。本申请中包含的大部分工作得到了目前NIH R 01对PI的资助，以及作为NIH R 01的一部分对匹兹堡大学药学院P. Friedman博士的新资助。在这个项目中，我们提出了分层联合收割机原子和粗粒度的蛋白质几何模拟开发一个有效的和实用的算法来计算潜在的平均力（PMF）沿着连接两个已知状态的反应坐标。为了设计和测试提出的方法的发展，我们需要进行广泛的MD模拟各种大小的蛋白质系统。以下章节中描述的一系列研究旨在使我们能够满足我们的两个目标：离子通道和受体的研究，以及更好地理解蛋白质灵活性和更准确的自由能计算的方法学开发。我们将继续使用我们的MD/FIRST方法（Mamonova et al. Phys. Biol. 2005）来鉴定蛋白质中的刚性和柔性区域，并将蛋白质结构的柔性与其功能特征相关联。作为原始项目的一部分，继续使用小球状蛋白作为测试示例来研究蛋白质的灵活性。我们将我们的研究扩展到模拟NHERF 1蛋白的PDZ结构域的配体-蛋白质相互作用，以及谷氨酸受体和钾通道中的自由能控制孔闭合，作为我们先前研究的扩展。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The research described in this proposal is continuation of projects previously supported by the NSF PACI grant #MCB040046 titled Molecular Simulations of the Ion Channel and Receptor proteins. In this application we request support for the second year of this multi-year award (04.01.2008-03.30.2010) and additional resources that are required due to expansion of our research projects. We are proposing to extend our studies to include additional systems and to test hypotheses which were formulated during our work in the previous period of funding. The majority of work included in this application is supported by current NIH R01 grant to PI, as well as a new funding to PI as a subcontract of an NIH R01 to Dr. P. Friedman of School of Pharmacy of the University of Pittsburgh. In this project we propose to hierarchically combine atomistic and coarse-grained geometric simulations of proteins to develop an efficient and practical algorithm to calculate potentials of mean force (PMF) along reaction coordinates connecting two known states. In order to design and test proposed methodological development we need to perform extensive MD simulations of protein systems of various sizes. The set of studies described in the following sections is designed such that it allows us to meet both our objectives: the study of ion channels and receptors, and methodology development for better understanding of protein flexibility and more accurate free energy calculations. We will continue to use our MD/FIRST methodology (Mamonova et al. Phys. Biol. 2005) to identify rigid and flexible regions in proteins and to correlate flexibility of protein structures with their functional characteristics. As a part of the original project investigation of the protein flexibility is continued using small globular proteins as test examples. We extend our studies to model ligand-protein interactions of the PDZ domains of NHERF1 protein, as well as free energy controlling pore closure in Glutamate Receptors and Potassium channels as an extension of our prior studies.