COMPUTATIONAL APPROACHES TO UNDERSTANDING BIOLOGICAL SYSTEMS

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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.