COMPUTATIONAL APPROACHES TO UNDERSTANDING BIOLOGICAL SYSTEMS

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 我们最初的目标是使用NAMD通过分子动力学方法(包括显式水分子)来模拟EGF激酶受体之间的相互作用。我们已经使用PDB文件1M17生产了一些药物分子复合体，它是埃洛替尼(Tarceva)与表皮生长因子受体酪氨酸激酶域的复合体。我们已经使用Autodock3生产了一些埃洛替尼类分子的络合物(20)，这些络合物的设计符合利平斯基的规则。初始分配的大部分将用于测试阶段，在该阶段将为该系统开发一套一致的工具，这些工具可以很容易地扩展到其他有希望的模拟系统。我们将使用本地资源使用高斯对配体进行参数化，但使用现有资源进行大型模拟是不可能的。我们还预计在未来使用Amber进行QM/MM计算，并希望对苹果酸脱氢酶等系统进行一些可行性测试，至少两个小组已经使用CHARMM进行了研究，但结果不同。

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. Our initial goal is to use NAMD to simulate the interaction of the EGF kinase receptor using molecular dynamics methods, including explicit water molecules. We have produced a number of drug molecule complexes using the PDB file 1M17 that is a complex of erlotinib (Tarceva) with the epidermal growth factor receptor tyrosine kinase domain. We have used Autodock3 to produce a number of complexes of erlotinib-like molecules (20) that have been designed to be in accord with Lipinskys rules. Most of the initial allotment will be used for a testing phase where a consistent set of tools will be developed for this system that can easily be expanded to other promising analogs. We will use local resources for parameterization of ligands using Gaussian, but it has not been possible to do our work doing large simulations with currently available resources. We also anticipate doing QM/MM calculations in the future, using AMBER, and wish to do some feasibility testing on systems such as malate dehydrogenase, that has been studied by at least two groups using CHARMM with different results.