Abstract

Membranes with their embedded ion channels play a crucial role in numerous cell processes such as: signaling, energy conversion, and ion conductance. The long term goal of the proposed studies is to provide a detailed understanding of the biophysical properties of biological membranes through molecular modeling using coarse grain modeling. Specifically, for this proposal, we aim to obtain a detailed description of oligomeric ion channel structure, dynamics and assembly while embedded within a membrane. Results of even a limited nature will promote public health by providing essential information needed for the rational design of novel antimicrobial, antiviral, and pharmaceutical agents which target ion channels. The knowledge gained may be use to enable mankind to combat many diseases and to alleviate some of the shortcomings currently encountered with today's therapeutics. We propose to elucidate salient mesoscale spatial (~ 1 The specific aims are a carefully planned series of simulations to examine the interactions of ion channels embedded within membranes:
Aim 1 is to understand the interaction of the ?-helical peptide within the bilayer;
Aim 2 is to understand the role and response of the lipid bilayer to the ? -helix;
Aim 3 is to understand the helix- helix interactions within an ion channel;
and Aim 4 is to calculate binding free energy (G) of formation of the ion channel. A common goal of all aims is to quantify the structural and dynamical properties of ion channels and their interactions with membranes. If these aims are successful (or even partially successful) we should gain insight into the mechanism of formation of homo-oligomeric ion channels from monomeric peptides.

Public Health Relevance

The aim of this proposal is to obtain a detailed description of oligomeric ion channel structure and dynamics embedded within a membrane. Completion of this aim will promote public health by providing essential information needed for the rational design of novel antimicrobial, antiviral, and pharmaceutical agents which target ion channels. The knowledge gained has the potential to further enable humans to combat many diseases and to alleviate some of the shortcomings currently encountered with today's therapeutics. ? ? ?

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Academic Research Enhancement Awards (AREA) (R15)
Project #
2R15GM075990-02
Application #
7523133
Study Section
Biochemistry and Biophysics of Membranes Study Section (BBM)
Program Officer
Chin, Jean
Project Start
2006-01-01
Project End
2010-12-30
Budget Start
2008-07-01
Budget End
2010-12-30
Support Year
2
Fiscal Year
2008
Total Cost
$227,760
Indirect Cost

  Institution

Name
University of the Sciences Philadelphia
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
079497681
City
Philadelphia
State
PA
Country
United States
Zip Code
19104

  Publications

Nguyen, Thuy Hien T; Liu, Zhiwei; Moore, Preston B (2013) Molecular dynamics simulations of homo-oligomeric bundles embedded within a lipid bilayer. Biophys J 105:1569-80
Pantano, Diego A; Klein, Michael L; Discher, Dennis E et al. (2011) Morphologies of charged diblock copolymers simulated with a neutral coarse-grained model. J Phys Chem B 115:4689-95
Nguyen, Thuy Hien T; Rao, Niny Z; Schroeder, William M et al. (2010) Coarse-grained molecular dynamics of tetrameric transmembrane peptide bundles within a lipid bilayer. Chem Phys Lipids 163:530-7
Kalescky, Robert J B; Shinoda, Wataru; Moore, Preston B et al. (2009) Area per ligand as a function of nanoparticle radius: a theoretical and computer simulation approach. Langmuir 25:1352-9