The research project described in the main grant proposed to use powerful new software tools that have been developed in our laboratory, to achieve its long term goal to gain new and deeper understanding of the determinants of functional action of protein segments in the context of the complete molecular system. Particular attention will be focused on understanding how protein segments in the G-Protein Coupled Receptors (GPCRs) respond to ligand binding and how and why these elements respond differently to distinctive classes of substances. The class of drugs with hallucinogenic properties will be of particular interest because molecular based insights into how they elicit responses in GPCRs that are different from those of non-hallucinogenic compounds, may provide clues for developing therapeutic agents that mitigate or neutralize the effects of hallucinogens. The long term goals of the main grant require that effort be fully directed to answering the structural and biological questions posed above. Because the main grant makes it difficult to expend effort on software development and dissemination, the main goals of this supplement are ? 1. To further develop and package for distribution stand-alone software that already has been written for the calculation of electrostatic effects in proteins and the quantitative description of protein inhomogeneity. ? 2. To further develop and prepare for incorporation of major new and novel software into existing software packages that already enjoy a wide distribution. This supplemented is being requested under program announcement PA-02-141 with goals to develop software packages consistent with the desirable attributes expected of contemporary software. These attributes include extensive documentation and description of the basic theoretical framework to help end users understand the purpose of the software and its limitations. Considerable attention will be directed to provide appropriate testing tools, ease of modification, extension and debugging. To facilitate these goals, the proposed work will be advised and guided by the Institute of Computational Biomedicine (ICB) of the Mount Sinai School of Medicine. The ICB will provide the expertise for developing properly packaged software for dissemination. ? ?
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