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. The research described in this proposal is continuation of projects previously supported by the NSF PACI grant #MCB040046 titled Molecular Simulations of the Ion Channel and Receptor proteins. In this application we request support for the second year of this multi-year award (04.01.2008-03.30.2010) and additional resources that are required due to expansion of our research projects. We are proposing to extend our studies to include additional systems and to test hypotheses which were formulated during our work in the previous period of funding. The majority of work included in this application is supported by current NIH R01 grant to PI, as well as a new funding to PI as a subcontract of an NIH R01 to Dr. P. Friedman of School of Pharmacy of the University of Pittsburgh. In this project we propose to hierarchically combine atomistic and coarse-grained geometric simulations of proteins to develop an efficient and practical algorithm to calculate potentials of mean force (PMF) along reaction coordinates connecting two known states. In order to design and test proposed methodological development we need to perform extensive MD simulations of protein systems of various sizes. The set of studies described in the following sections is designed such that it allows us to meet both our objectives: the study of ion channels and receptors, and methodology development for better understanding of protein flexibility and more accurate free energy calculations. We will continue to use our MD/FIRST methodology (Mamonova et al. Phys. Biol. 2005) to identify rigid and flexible regions in proteins and to correlate flexibility of protein structures with their functional characteristics. As a part of the original project investigation of the protein flexibility is continued using small globular proteins as test examples. We extend our studies to model ligand-protein interactions of the PDZ domains of NHERF1 protein, as well as free energy controlling pore closure in Glutamate Receptors and Potassium channels as an extension of our prior studies.
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