Computer Simulation of Amphiphilic Aggregates

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DESCRIPTION (provided by applicant): This competing renewal is requesting continuing support for the Klein group's computer simulation studies on membranes and membrane-bound species, with special emphasis on biophysical problems difficult to tackle with brute force application of standard codes. Specifically, the first aim is to extend our recently developed coarse grain (CG) simulation model for membranes to be able to explore the self-assembly of Ghadiri's membrane-active nanotubes composed of cyclic D, L-alpha-peptides. Of special interest, is the nature of the peptide - lipid membrane interactions, and the dependence on the choice of peptide amino acid residues and lipid composition. A key motif to be explored is the use of cyclic-peptide capping subunits to generate heteromeric assemblies with tailored properties. The second aim will use the CG model to study lipid sorting and membrane-mediated protein aggregation. The goal is to elucidate how proteins move lipids and lipids move proteins to alter the local bilayer membrane stability, thereby allowing for the curvatures required for vesicle budding and membrane fusion. The third aim is directed to understand how water soluble di-block copolymer micelles affect the translocation of synthetic hydrophobic molecules across biomembranes. The focus is on both the encapsulation by the polymer micelles and their interaction with lipid bilayers. In the fourth and final aim, new molecular dynamics simulation methodologies will be applied to gain insights into the mechanism of gating in ion channels. The first target will be the ClC chloride channel, whose structure was recently published by the MacKinnon group in both the closed and open states. These structures suggested a simple gating mechanism involving a conformational change of a single amino acid residue (Glu148) which, if correct, should be readily accessible to the new simulation methods. If the approach is indeed successful for this apparently simple example, it is proposed to tackle more difficult systems such as the acetylcholine receptor pore, for which Unwin has recently proposed a gating mechanism.