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Background.  Surfactant protein C (SP-C; 35 residues) in lungs has a cationic N-terminal domain with two cysteines covalently linked to palmitoyls and a C-terminal region enriched in Val, Leu and Ile. Native SP-C shows high surface activity, due to SP-C inserting in the bilayer with its cationic N-terminus binding to the polar headgroup and its hydrophobic C-terminus embedded as a tilted, transmembrane  α -helix. The palmitoylcysteines in SP-C act as ‘helical adjuvants’ to maintain activity by overriding the  β -sheet propensities of the native sequences.   Objective.  We studied SP-C peptides lacking palmitoyls, but containing glutamate and lysine at 4-residue intervals, to assess whether SP-C peptides with salt-bridges (“ion-locks”) promote surface activity by mimicking the  α -helix and membrane topography of native SP-C.   Methods.  SP-C mimics were synthesized that reproduce native sequences, but without palmitoyls (i.e., SP-Css or SP-Cff, with serines or phenylalanines replacing the two cysteines). Ion-lock SP-C molecules were prepared by incorporating single or double Glu − –Lys +  into the parent SP-C’s. The secondary structures of SP-C mimics were studied with Fourier transform infrared (FTIR) spectroscopy and PASTA, an algorithm that predicts  β -sheet propensities based on the energies of the various  β -sheet pairings. The membrane topography of SP-C mimics was investigated with orientated and hydrogen/deuterium (H/D) exchange FTIR, and also Membrane Protein Explorer (MPEx) hydropathy analysis.  In vitro  surface activity was determined using adsorption surface pressure isotherms and captive bubble surfactometry, and  in vivo  surface activity from lung function measures in a rabbit model of surfactant deficiency.   Results.  PASTA calculations predicted that the SP-Css and SP-Cff peptides should each form parallel  β -sheet aggregates, with FTIR spectroscopy confirming high parallel  β -sheet with ‘amyloid-like’ properties. The enhanced  β -sheet properties for SP-Css and SP-Cff are likely responsible for their low surfactant activities in the  in vitro  and  in vivo  assays. Although standard  12 C-FTIR study showed that the  α -helicity of these SP-C sequences in lipids was uniformly increased with Glu − –Lys +  insertions, elevated surfactant activity was only selectively observed. Additional results from oriented and H/D exchange FTIR experiments indicated that the high surfactant activities depend on the SP-C ion-locks recapitulating both the  α -helicity and the membrane topography of native SP-C. SP-Css ion-lock 1, an SP-Css with a salt-bridge for a Glu − –Lys +  ion-pair predicted from MPEx hydropathy calculations, demonstrated enhanced surfactant activity and a transmembrane helix simulating those of native SP-C.   Conclusion.  Highly active SP-C mimics were developed that replace the palmitoyls of SP-C with intrapeptide salt-bridges and represent a new class of synthetic surfactants with therapeutic interest.

peerj

Surfactant protein C peptides with salt-bridges (“ion-locks”) promote high surfactant activities by mimicking the<i>α</i>-helix and membrane topography of the native protein

Surfactant protein C peptides with salt-bridges (“ion-locks”) promote high surfactant activities by mimicking theα-helix and membrane topography of the native protein