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Does arginine remain protonated in the lipid membrane? Insights from microscopic pKa calculations.

ABSTRACT: Free energy perturbation calculations are carried out to estimate the effective pK(a) of an arginine (Arg) sidechain as a function of its location in the dipalmitoylphosphatidylcholine bilayer. Similar to previous all-atom simulations of the voltage sensor domain of a potassium channel in the membrane with charged Arg residues, the membrane and water structures deform to stabilize the charge of the Arg analog. As a result, the computed pK(a) is >7 throughout the membrane although the value is very close to 7 near the center of the bilayer. With additional stabilizations from negatively charged amino acids or lipid molecules, it is reasonable to expect that Arg in membrane proteins (once in the membrane) can adopt the protonated state despite the low dielectric nature of the bulk lipid membrane.

SUBMITTER: Yoo J

PROVIDER: S-EPMC2275699 | biostudies-literature | 2008 Apr

REPOSITORIES: biostudies-literature

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Does arginine remain protonated in the lipid membrane? Insights from microscopic pKa calculations.

Yoo Jejoong J Cui Qiang Q

Biophysical journal 20080116 8

Free energy perturbation calculations are carried out to estimate the effective pK(a) of an arginine (Arg) sidechain as a function of its location in the dipalmitoylphosphatidylcholine bilayer. Similar to previous all-atom simulations of the voltage sensor domain of a potassium channel in the membrane with charged Arg residues, the membrane and water structures deform to stabilize the charge of the Arg analog. As a result, the computed pK(a) is >7 throughout the membrane although the value is ve ...[more]

PMID: 18199662

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Project description:The self-assembly behavior and antimicrobial activity of two designed amphiphilic peptides, R3F3 and R4F4, containing short hydrophobic phenylalanine (F) and cationic arginine (R) sequences, are investigated. The conformation of the peptides was examined using circular dichroism and FTIR spectroscopy, which show that they have a disordered secondary structure. Concentration-dependent fluorescence assays show the presence of a critical aggregation concentration (cac) for each peptide. Above the cac, small-angle X-ray scattering (SAXS) and transmission electron microscopy (TEM) reveal a population of twisted tapes for R3F3 and nanosheets for R4F4. The interaction of the peptides with model bacterial membranes comprising mixtures of the lipids DPPG [1,2-dipalmitoyl-sn-glycero-3-phosphoglycerol] and DPPE [1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine], was studied using SAXS and cryogenic-TEM. Analysis of the SAXS structure factor indicates that R3F3 interacts with lipid bilayers by inducing correlation between bilayers, whereas R4F4 interacts with the bilayers causing an increase in polydispersity of the vesicle wall thickness. Both peptides break vesicles with a 1:3 DPPG:DPPE composition, which is close to the ratio of PG and PE lipids observed in the lipid membrane of Pseudomonas aeruginosa, a pathogen responsible for serious infections and which has developed antimicrobial resistant strains. Both peptides show activity against this bacterium in planktonic form. Peptide R4F4 shows particularly strong bioactivity against this microbe, with a minimum inhibitory concentration (MIC) value in the range of concentrations where the peptide is cytocompatible. It was further shown to have activity against other Pseudomonas species including the common plant pathogen Pseudomonas syringae. Finally, we show that R4F4 inhibits the development of P. aeruginosa biofilms. This was examined in detail and a proposed mechanism involving binding of the signaling molecule c-di-GMP is suggested, based on circular dichroism spectroscopy studies and Congo red assays of extracellular polysaccharides produced by the stressed bacteria. Thus, R4F4 is a promising candidate antimicrobial peptide with activity against Pseudomonas species.

Dataset Information

Does arginine remain protonated in the lipid membrane? Insights from microscopic pKa calculations.

Publications

Does arginine remain protonated in the lipid membrane? Insights from microscopic pKa calculations.

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