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Computational studies of protegrin antimicrobial peptides: a review.

ABSTRACT: Antimicrobial peptides (AMPs) are small, naturally occurring peptides that exhibit strong antibacterial properties generally believed to be a result of selective bacterial membrane disruption. As a result, there has been significant interest in the development of therapeutic antibiotics based on AMPs; however, the poor understanding of the fundamental mechanism of action of these peptides has largely hampered such efforts. We present a summary of computational and theoretical investigations of protegrin, a particularly potent peptide that is both an excellent model for the mechanism of action of AMPs and a promising therapeutic candidate. Experimental investigations have shed light on many of the key steps in the action of protegrin: protegrin monomers are known to dimerize in various lipid environments; protegrin peptides interact strongly with lipid bilayer membranes, particularly anionic lipids; protegrins have been shown to form pores in lipid bilayers, which results in uncontrolled ion transport and may be a key factor in bacterial death. In this work, we present a comprehensive review of the computational and theoretical studies that have complemented and extended the information obtained from experimental work with protegrins, as well as a brief survey of the experimental biophysical studies that are most pertinent to such computational work. We show that a consistent, mechanistic description of the bactericidal mechanism of action of protegrins is emerging, and briefly outline areas where the current understanding is deficient. We hope that the research reviewed herein offers compelling evidence of the benefits of computational investigations of protegrins and other AMPs, as well as providing a useful guide to future work in this area.

SUBMITTER: Bolintineanu DS

PROVIDER: S-EPMC3013618 | biostudies-literature | 2011 Jan

REPOSITORIES: biostudies-literature

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Computational studies of protegrin antimicrobial peptides: a review.

Bolintineanu Dan S DS Kaznessis Yiannis N YN

Peptides 20101012 1

Antimicrobial peptides (AMPs) are small, naturally occurring peptides that exhibit strong antibacterial properties generally believed to be a result of selective bacterial membrane disruption. As a result, there has been significant interest in the development of therapeutic antibiotics based on AMPs; however, the poor understanding of the fundamental mechanism of action of these peptides has largely hampered such efforts. We present a summary of computational and theoretical investigations of p ...[more]

PMID: 20946928

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Project description:Protegrin-1 (PG-1) is a cationic arginine-rich antimicrobial peptide. It is widely accepted that PG-1 induces membrane disruption by forming pores that lead to cell death. However, the insertion mechanism for these highly cationic peptides into the hydrophobic membrane environment is still poorly understood at the molecular scale. It has previously been determined that the association of arginine guanidinium and lipid phosphate groups results in strong bidentate bonds that stabilize peptide-lipid complexes. It has also been suggested that arginine residues are able to drag phosphate groups as they insert inside the membrane to form a toroidal pore. However, whether bidentate bonds play a significant role in inducing a pore formation remains unclear. To investigate the role of bidentate complexes in PG-1 translocation, we conducted molecular dynamics simulations. Two computational electroporation methods were implemented to examine the translocation process. We found that PG-1 could insert into the membrane, provided the external electric potential is large enough to first induce a water column or a pore within the lipid bilayer membrane. We also found that the highly charged PG-1 is capable in itself of inducing molecular electroporation. Substitution of arginines with charge-equivalent lysines showed a markedly reduced tendency for insertion. This indicates that the guanidinium group likely facilitates PG-1 translocation. Potential of mean force calculations suggests that peptide insertion inside the hydrophobic environment of the membrane core is not favored. We found that formation of a water column or a pore might be a prerequisite for PG-1 translocation. We also found that PG-1 can stabilize the pore after insertion. We suggest that PG-1 could be a pore inducer and stabilizer. This work sheds some light on PG-1 translocation mechanisms at the molecular level. Methods presented in this study may be extended to other arginine-rich antimicrobial and cell-penetrating peptides.

Project description:The structural basis for the gram selectivity of two disulfide-bonded ?-hairpin antimicrobial peptides (AMPs) is investigated using solid-state nuclear magnetic resonance (NMR) spectroscopy. The hexa-arginine PG-1 exhibits potent activities against both gram-positive and gram-negative bacteria, while a mutant of PG-1 with only three cationic residues maintains gram-positive activity but is 30-fold less active against gram-negative bacteria. We determined the topological structure and lipid interactions of these two peptides in a lipopolysaccharide (LPS)-rich membrane that mimics the outer membrane of gram-negative bacteria and in the POPE/POPG membrane, which mimics the membrane of gram-positive bacteria. (31)P NMR line shapes indicate that both peptides cause less orientational disorder in the LPS-rich membrane than in the POPE/POPG membrane. (13)C chemical shifts and (13)C-(1)H dipolar couplings show that both peptides maintain their ?-hairpin conformation in these membranes and are largely immobilized, but the mutant exhibits noticeable intermediate-time scale motion in the LPS membrane at physiological temperature, suggesting shallow insertion. Indeed, (1)H spin diffusion from lipid chains to the peptides shows that PG-1 fully inserts into the LPS-rich membrane whereas the mutant does not. The (13)C-(31)P distances between the most hydrophobically embedded Arg of PG-1 and the lipid (31)P are significantly longer in the LPS membrane than in the POPE/POPG membrane, indicating that PG-1 does not cause toroidal pore defects in the LPS membrane, in contrast to its behavior in the POPE/POPG membrane. Taken together, these data indicate that PG-1 causes transmembrane pores of the barrel-stave type in the LPS membrane, thus allowing further translocation of the peptide into the inner membrane of gram-negative bacteria to kill the cells. In comparison, the less cationic mutant cannot fully cross the LPS membrane because of weaker electrostatic attractions, thus causing weaker antimicrobial activities. Therefore, strong electrostatic attraction between the peptide and the membrane surface, ensured by having a sufficient number of Arg residues, is essential for potent antimicrobial activities against gram-negative bacteria. The data provide a rational basis for controlling gram selectivity of AMPs by adjusting the charge densities.

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Computational studies of protegrin antimicrobial peptides: a review.

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Computational studies of protegrin antimicrobial peptides: a review.

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