Hierarchical Modeling/Ion Channel and Receptor Mechanism

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DESCRIPTION (provided by applicant): Membrane proteins that function normally are vital to health; their defects are associated with many known disease states. Membrane proteins are the targets of many pharmacologically and toxicologically active substances and are responsible, in part, for the uptake, metabolism, and clearance of these substances. Despite the importance of membrane proteins, knowledge of their high-resolution structures and mechanisms of action has lagged far behind the knowledge of these properties of proteins in general. Theoretical modeling may help in deciphering the structure-function relationship of membrane proteins, however theoretical modeling of membrane proteins also lags behind the modeling of globular proteins. Our long-term goal in this proposed project is theoretical modeling of structure and function of membrane proteins to provide understanding of how the molecular and atomistic events during ion permeation and ligand binding lead to mesoscopic events of channel conductance and regulation. One problem in modeling ion channels is that characterizing their function, i.e. ion current - voltage relationships, requires modeling of processes on at least the microsecond time-scale, inaccessible for current atomistic simulations of proteins. The objective of this application is thus to create and apply reliable yet computationally efficient molecular-level models for ion permeation through open channels, which take into account channel protein molecular structure, polarizability and short time-scale flexibility, yet are capable of predicting observable ion currents (a slow process by Molecular Dynamics standards). In order to efficiently span a wide range of time-scales relevant to the ion permeation, the proposed models are of hierarchical nature. Our aims in this project are: to develop, test and apply hierarchical algorithms to model ion currents through open flexible channels of known or predicted 3D structures. In order to implement this hierarchical approach we will use several levels of resolution ("graining") of the system under consideration: from all-atom molecular modeling of the channel protein with its surrounding medium to coarse grained continuum approximate models, capable of spanning longer time-scales and mesoscopic sizes. Using this molecular/mesoscopic hierarchy of models we will study several systems of medical and medical engineering interest. We expect that the outcome of this proposed project will be significant for future direction of theoretical and computational approaches to study membrane proteins because once a functional model based on protein structure has been developed it will become possible to develop specific theoretical methodologies for designing drugs and drug delivery systems for membrane proteins via rational computer-aided design.