This component of the PPG is dedicated to quantitative, structural, and computational modelingaspects of our collaborative effort to understand the mechanisms of hallucinogenic drugs in varioustructural classes, triggered by their interactions with the subtypes of 5-HT GPCRs.
The aim tounderstand the mechanisms that engender the complex behavioral effects in hallucinogenesis, isbased on the hypothesis that the hallucinogenic potential of certain compounds results from specificmodes of interaction with these receptors, that produce distinct molecular signaling mechanisms;thus, hallucinogens trigger structural and dynamic receptor responses (affecting protein-proteininteractions) that differ from those produced by other ligands. This hypothesis leads to proposedinvestigations of (i) the modes of receptor response (conformational rearrangements andstabilization of 'activated state(s)') that trigger special protein-protein interactions ranging fromreceptor oligomerization to interactions with various scaffolding proteins (e.g., PDZ- BAR-domains),and (ii) how such conformational rearrangements and resulting association/dissociation of protein-protein interactions affect selectivity and efficiency in the signaling pathways of hallucinogens. Wedevelop and apply computational methods, modeling and simulation approaches (from structuralbiophysics, bioinformatics, predictive mathematical modeling) to study molecular and cellularsignaling systems involved in the mechanisms. The studies are closely coordinated with Projects 2and 3 of the PPG in which probing and validation of the models will be based on collaborativelydesigned experiments utilizing inferences, designs and protein constructs investigated in thisproject. These collaborative studies will serve to incorporate the structural context of molecularinteractions in systems level models of the hallucinogen signaling mechanisms. The components ofa hallucinogen signaling map will be stored in an information management system (SigPath)ultimately used to model quantitatively the pathways and learn about their characteristic properties,and their integration in the cellular machinery. We plan to start with modest, scientificallyresponsible simulations of small pathway elements in order to support hypothesis testing anddesign of experiments in the PPG that explore such pathways.
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