Molecular Dynamics Simulations of Oligomeric Ion Channels within Lipid Bilayers

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DESCRIPTION (provided by applicant): 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 <m) and temporal (~ 1 ms) features of membrane associated ion channels using coarse grain molecular modeling, such as the mechanism of formation from monomeric units which is hypothesized to occur in a stepwise fashion. Currently, these spatial and temporal regions are difficult to determine either experimentally or with conventional simulation methodologies. Coarse grain methods allow us to elucidate fundamental membrane mechanisms such as oligomerization, and the effect of membrane composition on structure and function of ion channels. 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.