High-resolution structures and orientations of antimicrobial peptides piscidin 1 and piscidin 3 in fluid bilayers reveal tilting, kinking, and bilayer immersion.

 In
by B Scott Perrin, Ye Tian, Riqiang Fu, Christopher V Grant, Eduard Y Chekmenev, William E Wieczorek, Alexander E Dao, Robert M Hayden, Caitlin M Burzynski, Richard M Venable, Mukesh Sharma, Stanley J Opella, Richard W Pastor, Myriam L Cotten
Abstract:
While antimicrobial peptides (AMPs) have been widely investigated as potential therapeutics, high-resolution structures obtained under biologically relevant conditions are lacking. Here, the high-resolution structures of the homologous 22-residue long AMPs piscidin 1 (p1) and piscidin 3 (p3) are determined in fluid-phase 3:1 phosphatidylcholine/phosphatidylglycerol (PC/PG) and 1:1 phosphatidylethanolamine/phosphatidylglycerol (PE/PG) bilayers to identify molecular features important for membrane destabilization in bacterial cell membrane mimics. Structural refinement of (1)H-(15)N dipolar couplings and (15)N chemical shifts measured by oriented sample solid-state NMR and all-atom molecular dynamics (MD) simulations provide structural and orientational information of high precision and accuracy about these interfacially bound $alpha$-helical peptides. The tilt of the helical axis, $tau$, is between 83° and 93° with respect to the bilayer normal for all systems and analysis methods. The average azimuthal rotation, $rho$, is 235°, which results in burial of hydrophobic residues in the bilayer. The refined NMR and MD structures reveal a slight kink at G13 that delineates two helical segments characterized by a small difference in their $tau$ angles (textless10°) and significant difference in their $rho$ angles (~25°). Remarkably, the kink, at the end of a G(X)4G motif highly conserved among members of the piscidin family, allows p1 and p3 to adopt $rho$ angles that maximize their hydrophobic moments. Two structural features differentiate the more potent p1 from p3: p1 has a larger $rho$ angle and less N-terminal fraying. The peptides have comparable depths of insertion in PC/PG, but p3 is 1.2 Å more deeply inserted than p1 in PE/PG. In contrast to the ideal $alpha$-helical structures typically assumed in mechanistic models of AMPs, p1 and p3 adopt disrupted $alpha$-helical backbones that correct for differences in the amphipathicity of their N- and C-ends, and their centers of mass lie ~1.2-3.6 Å below the plane defined by the C2 atoms of the lipid acyl chains.
Reference:
High-resolution structures and orientations of antimicrobial peptides piscidin 1 and piscidin 3 in fluid bilayers reveal tilting, kinking, and bilayer immersion. (B Scott Perrin, Ye Tian, Riqiang Fu, Christopher V Grant, Eduard Y Chekmenev, William E Wieczorek, Alexander E Dao, Robert M Hayden, Caitlin M Burzynski, Richard M Venable, Mukesh Sharma, Stanley J Opella, Richard W Pastor, Myriam L Cotten), In Journal of the American Chemical Society, volume 136, 2014.
Bibtex Entry:
@article{Perrin2014,
abstract = {While antimicrobial peptides (AMPs) have been widely investigated as potential therapeutics, high-resolution structures obtained under biologically relevant conditions are lacking. Here, the high-resolution structures of the homologous 22-residue long AMPs piscidin 1 (p1) and piscidin 3 (p3) are determined in fluid-phase 3:1 phosphatidylcholine/phosphatidylglycerol (PC/PG) and 1:1 phosphatidylethanolamine/phosphatidylglycerol (PE/PG) bilayers to identify molecular features important for membrane destabilization in bacterial cell membrane mimics. Structural refinement of (1)H-(15)N dipolar couplings and (15)N chemical shifts measured by oriented sample solid-state NMR and all-atom molecular dynamics (MD) simulations provide structural and orientational information of high precision and accuracy about these interfacially bound $alpha$-helical peptides. The tilt of the helical axis, $tau$, is between 83° and 93° with respect to the bilayer normal for all systems and analysis methods. The average azimuthal rotation, $rho$, is 235°, which results in burial of hydrophobic residues in the bilayer. The refined NMR and MD structures reveal a slight kink at G13 that delineates two helical segments characterized by a small difference in their $tau$ angles ({textless}10°) and significant difference in their $rho$ angles ({~{}}25°). Remarkably, the kink, at the end of a G(X)4G motif highly conserved among members of the piscidin family, allows p1 and p3 to adopt $rho$ angles that maximize their hydrophobic moments. Two structural features differentiate the more potent p1 from p3: p1 has a larger $rho$ angle and less N-terminal fraying. The peptides have comparable depths of insertion in PC/PG, but p3 is 1.2 {AA} more deeply inserted than p1 in PE/PG. In contrast to the ideal $alpha$-helical structures typically assumed in mechanistic models of AMPs, p1 and p3 adopt disrupted $alpha$-helical backbones that correct for differences in the amphipathicity of their N- and C-ends, and their centers of mass lie {~{}}1.2-3.6 {AA} below the plane defined by the C2 atoms of the lipid acyl chains.},
author = {Perrin, B Scott and Tian, Ye and Fu, Riqiang and Grant, Christopher V and Chekmenev, Eduard Y and Wieczorek, William E and Dao, Alexander E and Hayden, Robert M and Burzynski, Caitlin M and Venable, Richard M and Sharma, Mukesh and Opella, Stanley J and Pastor, Richard W and Cotten, Myriam L},
doi = {10.1021/ja411119m},
issn = {1520-5126},
journal = {Journal of the American Chemical Society},
month = {mar},
number = {9},
pages = {3491--504},
pmid = {24410116},
title = {{High-resolution structures and orientations of antimicrobial peptides piscidin 1 and piscidin 3 in fluid bilayers reveal tilting, kinking, and bilayer immersion.}},
url = {http://pubs.acs.org/doi/abs/10.1021/ja411119m http://www.ncbi.nlm.nih.gov/pubmed/24410116 http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=PMC3985945},
volume = {136},
year = {2014}
}

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