Thesis (Ph.D.)--University of Rochester. School of Medicine & Dentistry. Dept. of Biochemistry and Biophysics, 2013.
Phospholipid bilayers are critical components of living organisms. They organize
into membranes that encapsulate the contents of cells and organelles, compartmentalizing
cellular function and separating these from the extracellular medium.
Similarly, peptides play a huge role as structural and functional components of
nearly all biological processes. The interplay between the two is a major area of
research: how peptides interact with and alter lipid bilayers and how lipids regulate
the structure and function of folded peptides.
One exciting tool for analyzing peptide-lipid interactions comes in the form
of molecular dynamics, a simulation method that approximates the interactions of
molecules at the atomic level, producing trajectories of molecular motion over time.
This contributes unique insight into peptide-lipid interactions by providing a level
of detail that is rare in experimental work.
Antimicrobial peptides form a particularly interesting class of peptides that affect
membranes. These short peptides target and permeabilize primarily bacterial
membranes, often resulting in cell death. Their simplicity makes them ideal candidates
for a novel class of antibiotics. However, initial limitations led others to
develop synthetic antimicrobial lipopeptides that are even simpler and cheaper to
produce, while retaining many of the characteristic antimicrobial properties. Molecular
dynamics was used to quantify the membrane activity of one such antimicrobial
peptide, C16-KGGK, and a naturally occurring antifungal peptide, fengycin.
Due to the high computational cost of traditional all-atom molecular dynamics,
a coarse-grained approach was employed where groups of atoms that form a
functional unit are treated as one bead. The simulations demonstrated bilayer preferences,
lipid demixing properties, and peptide-induced bilayer perturbations. This
allowed for the development of a hypothesized model of action for C16-KGGK and
provided some new insights into the activity of fengycin.
Finally, simulation was also used to understand lipid packing against the integral
membrane protein rhodopsin. It is known that lipid environment affects rhodopsin
activation, but specific interactions are not currently known. These simulations
showed possible cholesterol binding sites and highlighted a preference at the surface
of the protein for specific lipid tails and lipid headgroups.
National Institute of General Medical Sciences (NIGMS) - GM068411 through the University of Rochester’s T32 Training Program via the Institutional Ruth L. Kirschstein National Research Service Award; GM095496 awarded to Dr. Alan Grossfield
First presented to the public:
10/11/2014
Originally created:
2013
Date will be made available to public:
2014-10-11
Original Publication Date:
2013
Previously Published By:
University of Rochester School of Medicine and Dentistry
Place Of Publication:
Rochester, N.Y.
Citation:
Extents:
Number of Pages - xxiii, 215 p.
License Grantor / Date Granted:
Susan Love
/ 2013-10-22 09:36:11.478 ( View License )
