COMPUTATIONAL INVESTIGATION OF INHIBITOR BINDING TO THE ENZYME SARCO/ENDOPLASMI

这个子项目是利用这些资源的众多研究子项目之一

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.