COMPUTATIONAL APPROACHES TO UNDERSTANDING BIOLOGICAL SYSTEMS

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。 我们的初步目标是使用NAMD模拟EGF激酶受体的相互作用，使用分子动力学方法，包括明确的水分子。我们已经使用PDB文件1 M17生产了许多药物分子复合物，该PDB文件1 M17是厄洛替尼（Tarceva）与表皮生长因子受体酪氨酸激酶结构域的复合物。我们已经使用Autodock 3产生了许多埃洛替尼样分子的复合物（20），其被设计为符合Lipinskys规则的雅阁。最初分配的大部分资金将用于测试阶段，在此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前途的类似物。我们将使用本地资源使用高斯配体的参数化，但它一直不可能做我们的工作做大规模的模拟与目前可用的资源。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，至少有两个小组使用CHARMM进行了研究，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.