Computational Study of Helical and Helix-Hinge-Helix Conformations of an Anti-Microbial Peptide in Solution by Molecular Dynamics and Vibrational Analysis.

Many classical antimicrobial peptides adopt an amphipathic helical structure at a water-membrane interface. Prior studies led to the hypothesis that a hinge near the middle of a helical peptide plays an important role in facilitating peptide-membrane interactions. Here, dynamics and vibrations of a designed hybrid antimicrobial peptide LM7-2 in solution were simulated to investigate its hinge formation. Molecular dynamics simulation results on the basis of the CHARMM36 force field showed that the α-helix LM7-2 bent around two or three residues near the middle of the peptide, stayed in a helix-hinge-helix conformation for a short period of time, and then returned to a helical conformation. High-resolution computational vibrational techniques were applied on the LM7-2 system when it has α-helical and helix-hinge-helix conformations to understand how this structural change affects its inherent vibrations. These studies concentrated on the calculation of frequencies that correspond to backbone amide bands I, II, and III: vibrational modes that are sensitive to changes in the secondary structure of peptides and proteins. To that end, Fourier transforms were applied to thermal fluctuations in C-N-H angles, C-N bond lengths, and C═O bond lengths of each amide group. In addition, instantaneous all-atom normal mode analysis was applied to monitor and detect the characteristic amide bands of each amide group within LM7-2 during the MD simulation. Computational vibrational results indicate that shapes and frequencies of amide bands II and especially III were altered only for amide groups near the hinge. These methods provide high-resolution vibrational information that can complement spectroscopic vibrational studies. They assist in interpreting spectra of similar systems and suggest a marker for the presence of the helix-hinge-helix motif. Moreover, radial distribution functions indicated an increase in the probability of hydrogen bonding between water and a hydrogen atom connected to nitrogen (HN) in such a hinge. The probability of intramolecular hydrogen bond formation between HN and an amide group oxygen atom within LM7-2 was lower around the hinge. No correlation has been found between the presence of a hinge and hydrogen bonds between amide group oxygen atoms and the hydrogen atoms of water molecules. This result suggests a mechanism for hinge formation wherein hydrogen bonds to oxygen atoms of water replace intramolecular hydrogen bonds as the peptide backbone folds.