Modeling the Effects of Hydrogen-Bond Disrupting Solvents on the Structure of Model Peptide Antibiotics

Abstract

The increase in antibiotic resistant infections is a serious threat to public health. Peptide antibiotics, which can perturb the cell membrane, offer one promising solution. We are investigating the structural properties of peptide antibiotic models composed of the hydrophobic dialkylated amino acid Aib (α-aminoisobutyric acid), which imparts a strong 310-helical bias due to steric hindrance at the α-carbon. Previous studies have shown that insertion of adjacent neutral monoalkylated amino acids into an Aib sequence creates a region of the helix that is highly sensitive to disruption of hydrogen bonds by strongly hydrogen-bonding solvents. In particular, the chemical shift of the amide hydrogen at position six of the octameric peptide AA45, which has two adjacent alanines in the center of the helix, is highly sensitive to the concentration of DMSO. Smaller changes in chemical shift are also observed at position seven on the helix. In this study, we have developed a thermodynamic model that describes the solvent-enabled disruption of internal hydrogen bonds within the helix as a function of DMSO concentration. We observe that the unusual concavity of the titration curve for the amide hydrogen at position six can be modeled as the result of DMSO-driven disruption of the hydrogen bond in the presence of competing hydrogen bonds with the surrounding solvent (chloroform). In addition, we compare the results of this model with NMR structures for the corresponding Aib helix and find that the behavior of the amide hydrogen at both positions six and seven is consistent with the formation of a kink in the helix at that position.