Tilted State Population of Antimicrobial Peptide PGLa Is Coupled to the Transmembrane Potential.

Cationic antimicrobial peptide PGLa gets into close contact with the anionic bacterial cell membrane, facilitating cross-membrane transport phenomena and membrane disruption depending on the concentration. The mechanisms of action are closely associated with the tilted insertion geometry of PGLa. Therefore, we aimed to understand the interaction between the transmembrane potential (TMP) and the orientation of the membrane-bound PGLa helix. Molecular dynamics simulations were performed with TMP, and we found that the PGLa tilt angle relative to the membrane is coupled with the TMP. Elevated TMP increases the population of the tilted state. We observed positive feedback between the tilt angle and the TMP, which occurs due to the electrostatic interaction between the peptidic helix and the Na+ cations at the membrane-water interface. These TMP coupled phenomena can contribute to understanding the direct antimicrobial and adjuvant effects of PGLa in combination with regular antibiotics.

Induced folding of protein-sized foldameric ß-sandwich models with core ß-amino acid residues.

The mimicry of protein-sized ß-sheet structures with unnatural peptidic sequences (foldamers) is a considerable challenge. In this work, the de novo designed betabellin-14 ß-sheet has been used as a template, and αâ†’ß residue mutations were carried out in the hydrophobic core (positions 12 and 19). ß-Residues with diverse structural properties were utilized: Homologous ß(3) -amino acids, (1R,2S)-2-aminocyclopentanecarboxylic acid (ACPC), (1R,2S)-2-aminocyclohexanecarboxylic acid (ACHC), (1R,2S)-2-aminocyclohex-3-enecarboxylic acid (ACEC), and (1S,2S,3R,5S)-2-amino-6,6-dimethylbicyclo[3.1.1]heptane-3-carboxylic acid (ABHC). Six α/ß-peptidic chains were constructed in both monomeric and disulfide-linked dimeric forms. Structural studies based on circular dichroism spectroscopy, the analysis of NMR chemical shifts, and molecular dynamics simulations revealed that dimerization induced ß-sheet formation in the 64-residue foldameric systems. Core replacement with (1R,2S)-ACHC was found to be unique among the ß-amino acid building blocks studied because it was simultaneously able to maintain the interstrand hydrogen-bonding network and to fit sterically into the hydrophobic interior of the ß-sandwich. The novel ß-sandwich model containing 25 % unnatural building blocks afforded protein-like thermal denaturation behavior.

Predicting order and disorder for ß-peptide foldamers in water.

Following a quantitative validation approach, we tested the AMBER ff03 and GAFF force fields with the TIP3P explicit water model in molecular dynamic simulations of ß-peptide foldamers. The test sequences were selected to represent a wide range of folding behavior in water: compact helix, strand mimetic geometry, and the state of disorder. The combination AMBER ff03-TIP3P successfully predicted the experimentally observed conformational properties and reproduced the NOE distances and backbone (3)J coupling data at a good level. GAFF was unable to produce folded structures correctly due to its biased torsion potentials. We can recommend AMBER ff03-TIP3P for simulations involving ß-peptide sequences in aqueous media including ordered and disordered structures.