%0 Journal Article %1 perrin_high-resolution_2014 %A Perrin, B Scott %A Tian, Ye %A Fu, Riqiang %A Grant, Christopher V %A Chekmenev, Eduard Y %A Wieczorek, William E %A Dao, Alexander E %A Hayden, Robert M %A Burzynski, Caitlin M %A Venable, Richard M %A Sharma, Mukesh %A Opella, Stanley J %A Pastor, Richard W %A Cotten, Myriam L %D 2014 %J J. Am. Chem. Soc. %K Antimicrobial Cationic Crystals,Molecular Dynamics Hydrophilic Interactions,Immersion,Lipid Peptides,Fish Proteins,Hydrophobic Simulation,Phosphatidylcholines,Phosphatidylglycerols,Protein Structure,Secondary and bilayers,Liquid %N 9 %P 3491--3504 %R 10.1021/ja411119m %T High-resolution structures and orientations of antimicrobial peptides piscidin 1 and piscidin 3 in fluid bilayers reveal tilting, kinking, and bilayer immersion %V 136 %X 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 (\$\backslash$textasciitilde\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 \$\backslash$textasciitilde\1.2-3.6 \AA below the plane defined by the C2 atoms of the lipid acyl chains.

@article{perrin_high-resolution_2014, 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 ({\{}$\backslash$textasciitilde{\}}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 {\{}$\backslash$textasciitilde{\}}1.2-3.6 {\AA} below the plane defined by the C2 atoms of the lipid acyl chains.}, added-at = {2017-03-14T02:48:56.000+0100}, 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}, biburl = {https://www.bibsonomy.org/bibtex/2465697b5906d5f7ac9ea3ebfc2133f2e/nmrresource}, doi = {10.1021/ja411119m}, interhash = {2077751c690a2701417043ab600627cb}, intrahash = {465697b5906d5f7ac9ea3ebfc2133f2e}, issn = {1520-5126}, journal = {J. Am. Chem. Soc.}, keywords = {Antimicrobial Cationic Crystals,Molecular Dynamics Hydrophilic Interactions,Immersion,Lipid Peptides,Fish Proteins,Hydrophobic Simulation,Phosphatidylcholines,Phosphatidylglycerols,Protein Structure,Secondary and bilayers,Liquid}, month = mar, number = 9, pages = {3491--3504}, pmid = {24410116}, timestamp = {2017-03-14T02:49:21.000+0100}, title = {{High-resolution structures and orientations of antimicrobial peptides piscidin 1 and piscidin 3 in fluid bilayers reveal tilting, kinking, and bilayer immersion}}, volume = 136, year = 2014 }