| dc.description.abstract | The passive permeation of small peptides across lipid bilayers was studied by using molecular dynamics simulations and umbrella sampling. The knowledge gained in this work furthers our understanding of permeation across cell membranes and provides insight into the intelligent design of future pharmaceutical compounds. The passive permeation of the three resonant amino acids – phenylalanine, tyrosine, and tryptophan – in blocked form was studied in a bilayer consisting of 50 DOPC lipid molecules. The potential of mean force displays a free energy minimum at the interface, followed by an energy barrier at the center of the bilayer. Translational diffusion constants are surprisingly flat; however, the reorientation of the entire molecule and the amino acid sidechains indicates a significant rotational barrier. A conformational and clustering analysis of phi, psi, chi-1, and chi-2 angles demonstrates that each amino acid adopts different conformations based upon its bilayer depth. Radial distribution functions, coordination numbers, and the number of solvating water molecules were also examined. The phenylalanine dipeptide was then studied as it permeates lipid bilayers consisting of either 50 DOPC, 50 POPC, or 40 POPC lipid molecules. DOPC lipid molecules are more disordered than POPC lipids. In DOPC, the potential of mean force is therefore broader and more rotational conformations were sampled. All other analyses confirmed our prior, general observations and were surprisingly insensitive to either lipid type or system size. Position dependent diffusion constants were then calculated for the permeation of the phenylalanine dipeptide using the Fluctuation-Dissipation theorem, Green-Kubo expressions, Einstein relations, the Hummer Displacement method, and a numerical approximation to the Smoluchowski equation. We found the numerical approximation method to be the most reliable, although the Fluctuation-Dissipation theorem also yields acceptable results when unconstrained simulations were conducted. Finally, the prior analyses were applied to the permeation of wh5, one of the smallest peptides capable of forming an alpha helix. For most of the permeation process, the alpha helix remains intact and only begins to unravel at select distances in the aqueous region and at the center of the lipid bilayer. The presence of the lipid bilayer influences the tertiary structure of wh5. | |
