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Antimicrobial
Peptides
Antimicrobial
peptides are molecules produced by the immune system of animals and plants
are being considered potential novel antibiotic candidates to combat emerging
drug-resistant bacterial strains. The peptides are known to kill bacterial
cells by direct membrane attack. Peptide membrane systems are not pliable
from crystallization and invariable involve a large number of interacting
molecules. Knowledge from X-ray and NMR experiments has been therefore
restricted. As a result, the mechanism of action of the peptides is not
yet clear. We work towards designing and implementing computational solutions
to fill the void.
Protegrins
 Protegrin-1
is an 18-residue b -hairpin peptide that belongs to the cathelicidin
class of antimicrobial peptides (AMPs). PG-1 has broad spectrum antimicrobial
properties; however, it is also toxic to humans. Robert Lehrer at UCLA
has created 60 analogues of this naturally occurring AMP. By using
molecular dynamics simulations to study protegrin-1 (PG-1) and its
analogues, we hope to determine the mechanism of its antimicrobial
activity. In order to mimic mammalian and bacterial cell membranes,
we use dodecylphosphocholine (DPC) and sodium dodecylphosphate (SDS)
micelles. Simulations with PG-1 in an SDS micelle have been carried
out to 13ns and a similar simulation in DPC has been performed for
50ns. From these simulations, we have determined that PG-1 has different
mechanisms of interaction with bacterial and mammalian membrane mimics.
This information has provided us with points of interest on the sequence
that may be mutated to obtain a peptide that is biologically active,
but also safe for use in humans.
 Ovispirins
Ovispirin-1 is an a-helical peptide that belongs
to the cathelicidins class of peptides: a mammalian family of antimicrobials
having a wide range of activity. In order to elucidate the cytolytic mechanism
of ovispirin-1 at the molecular level, we have carried out molecular dynamics
simulations of the peptide in pure lipid bilayers composed of zwitterionic
dimyristoyl phosphatidycholine (DMPC) and anionic dimyristoyl phosphatidylglycerol
(DMPG) lipids. PC and PG lipids are major components of mammalian and
bacterial inner membranes respectively. Differences in their chemical
nature are believed to be responsible for the bacterial specificity of
antimicrobial peptides. The 36,000-atom peptide-water-lipid system has
been simulated using CHARMM. Initial results indicate a very strong electrostatic
interaction of the peptide with DMPG bilayers, which led to large-scale
lipid disordering, and significant disruption of the lipid bilayer. Lys-1,
Lys-9 and Arg-5, which constitute a positively charged face at the helix
N-terminus, interacted strongly with the negatively charged head groups
of DMPG lipids. We observed no specific interactions between the peptide
and DMPC lipids.
These
observations distinctly illustrate the differential modes of interaction of the peptide with DMPG and DMPG
bilayers. We will carry out similar simulations with the peptides novispirin
T7 and novispirin G10, which are single-residue mutants of ovispirin with
reduced hemolytic properties. A detailed comparative examination of the
behavior of three peptides in DMPG and DMPC bilayers will be a big stride
forward in understanding peptide-lipid interactions. Such molecular level
insight into the modes of peptide-membrane interaction will enable the
rational design and engineering of peptides as potential antimicrobial
agents of therapeutic value.
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