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 i n 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. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM067962-04
Application #
7386028
Study Section
Biophysical Chemistry Study Section (BBCB)
Program Officer
Preusch, Peter C
Project Start
2005-04-01
Project End
2010-03-31
Budget Start
2008-04-01
Budget End
2009-03-31
Support Year
4
Fiscal Year
2008
Total Cost
$193,221
Indirect Cost
Name
Carnegie-Mellon University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
052184116
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Simakov, Nikolay A; Kurnikova, Maria G (2018) Membrane Position Dependency of the pKa and Conductivity of the Protein Ion Channel. J Membr Biol 251:393-404
Yonkunas, Michael; Kurnikova, Maria (2015) The Hydrophobic Effect Contributes to the Closed State of a Simplified Ion Channel through a Conserved Hydrophobic Patch at the Pore-Helix Crossing. Front Pharmacol 6:284
Yonkunas, Michael; Kurnikova, Maria (2011) Characterizing the energetic states of the GluR2 ligand binding domain core-dimer. Biophys J 100:L5-7
Simakov, Nikolay A; Kurnikova, Maria G (2010) Soft wall ion channel in continuum representation with application to modeling ion currents in ýý-hemolysin. J Phys Chem B 114:15180-90
Mamonova, Tatyana B; Glyakina, Anna V; Kurnikova, Maria G et al. (2010) Flexibility and mobility in mesophilic and thermophilic homologous proteins from molecular dynamics and FoldUnfold method. J Bioinform Comput Biol 8:377-94
Speranskiy, K; Kurnikova, M G (2009) Modeling of peptides connecting the ligand-binding and transmembrane domains in the GluR2 glutamate receptor. Proteins 76:271-80
Widge, Alik S; Matsuoka, Yoky; Kurnikova, Maria (2008) Development and initial testing of an empirical forcefield for simulation of poly(alkylthiophenes). J Mol Graph Model 27:34-44
Cheng, Mary Hongying; Coalson, Rob D; Cascio, Michael et al. (2008) Computational prediction of ion permeation characteristics in the glycine receptor modified by photo-sensitive compounds. J Comput Aided Mol Des 22:563-70
Mamonova, Tatyana; Yonkunas, Michael J; Kurnikova, Maria G (2008) Energetics of the cleft closing transition and the role of electrostatic interactions in conformational rearrangements of the glutamate receptor ligand binding domain. Biochemistry 47:11077-85
Liu, Zhenyu; Ramanoudjame, Gomathi; Liu, Deqian et al. (2008) Overexpression and functional characterization of the extracellular domain of the human alpha1 glycine receptor. Biochemistry 47:9803-10

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