COMPUTATIONAL INVESTIGATION OF INHIBITOR BINDING TO THE ENZYME SARCO/ENDOPLASMI

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 肌浆网/内质网钙-ATP酶（SERCA）抑制剂是研究酶在生理过程中作用的有价值的研究工具，并且它们也具有开发成抗前列腺癌剂的潜力。合成了一系列对苯二酚衍生物，一类新的SERCA抑制剂，并在生物测定中评估了它们抑制酶的能力。分子动力学模拟计划，这将有助于确定这些抑制剂在SERCAs结合位点的结合模式，这反过来，将允许确定关键的酶/抑制剂的相互作用。从模拟中获得的信息将指导未来合成具有改进性能的新型化合物。由于模拟的计算要求超过了我们在北方肯塔基州大学可用的资源，我们希望被授予访问TeraGrid超级计算机设施。SERCA酶系统的分子动力学模拟是一项计算机密集型的工作。确定具有并行高效多核处理的超级计算设备（如TeraGrid超级计算设备）是满足我们计算需求的最佳方式。SERCA/抑制剂/膜/水系统由约50，000个原子组成，系统需要模拟不少于5 ns以研究抑制剂/SERCA相互作用机制。此外，为了对结果有统计上的信心，我们需要在不同的初始条件下运行许多模拟。我们已经在双四核工作站上进行了系统的测试运行，该工作站使用了MPI并行环境和Charmm包中的并行功能。这个初步的练习给了我们一个可管理的计算时间为2周的一个系统的运行，我们计划执行系统的进一步模拟。此外，药物样抑制剂化合物需要在开始MD模拟之前使用量子力学包（诸如高斯）进行参数化和优化。最初，我们希望使用TeraGrid超级计算中心的高斯计算化学包进行研究。参数化和优化需要对大约25个原子的化合物进行MP2水平的量子模拟，具体来说，我们需要运行势能面和能量优化。我们寻求计算设施作为TeraGrid中的启动分配，以运行我们的高斯脚本，用于SERCA/抑制剂系统的分子动力学模拟的参数优化。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Inhibitors of the enzyme sarco/endoplasmic reticulum calcium-ATPase (SERCA) are valuable research tools for the study of the enzymes role in physiological processes and they also have the potential of being developed into agents against prostate cancer. A series of hydroquinone derivatives, a new class of SERCA inhibitors, have been synthesized and their ability to inhibit the enzyme has been assessed in bioassays. Molecular dynamics simulations are planned that will help identify the binding mode of these inhibitors in SERCAs binding site, which, in turn, will allow the determination of crucial enzyme/inhibitor interactions. Information gained from the simulations will guide the future synthesis of novel compounds with improved properties. Since the computational requirements for the simulations exceed the resources available to us at Northern Kentucky University, we hope to be granted access to the TeraGrid supercomputer facility. The molecular dynamics simulations of SERCA enzyme system is a highly computer intensive effort. Identifying a supercomputing facility with parallel efficient multi-core processing such as the TeraGrid supercomputing facility is the best way to address our computing needs.The SERCA/inhibitor/membrane/water system consists of ~50,000 atoms and the system needs to be simulated for not less than 5ns in order to study the inhibitor/SERCA interacting mechanism. Moreover, to have statistical confidence in the results we need to run many simulations with distinct initial conditions. We have already performed a test run of the system in dual-quad core workstation, which uses a MPI parallel environment and parallel capabilities in the Charmm package. This preliminary exercise gave us a manageable computing time of 2 weeks for a one run of the system and we plan to perform further simulations of the system. Furthermore, the drug-like inhibitor compounds needs to be parametrized and optimized using Quantum Mechanics package such as Gaussian prior to start the MD simulations. Initially, we expect to use Gaussian computational chemistry package in TeraGrid supercomputing center for our research. The parametrization and optimization need the quantum simulations of about 25 atoms compounds with MP2 level and specifically, we need to run potential energy surfaces and energy optimizations. We seek the computing facility as a startup allocation in TeraGrid to run our Gaussian script for the parameters optimization for Molecular Dynamics simulations of the SERCA/inhibitor systems.