2mcv
Solid-state NMR structure of piscidin 1 in aligned 1:1 phosphatidylethanolamine/phosphoglycerol lipid bilayers
Structural highlights
FunctionMORO_MORSA Exhibits broad spectrum antimicrobial activity against Gram-positive and Gram-negative bacteria as well as against a variety of fungi. Has hemolytic activity. Seems to disrupt the membranes by adopting an alpha helical conformation and forming toroidal pores.[1] [2] Publication Abstract from PubMedWhile 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 1H-15N dipolar couplings and 15N 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 degrees and 93 degrees with respect to the bilayer normal for all systems and analysis methods. The average azimuthal rotation, rho, is 235 degrees , 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 (<10 degrees ) and significant difference in their rho angles ( approximately 25 degrees ). 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 A 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 approximately 1.2-3.6 A below the plane defined by the C2 atoms of the lipid acyl chains. High-Resolution Structures and Orientations of Antimicrobial Peptides Piscidin 1 and Piscidin 3 in Fluid Bilayers Reveal Tilting, Kinking, and Bilayer Immersion.,Perrin BS Jr, Tian Y, Fu R, Grant CV, Chekmenev EY, Wieczorek WE, Dao AE, Hayden RM, Burzynski CM, Venable RM, Sharma M, Opella SJ, Pastor RW, Cotten ML J Am Chem Soc. 2014 Jan 22. PMID:24410116[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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