(426g) Inferring Effects of Sequence on Structure of Anti-Microbial Peptides through Molecular Dynamics and Normal Mode Analysis

Interest in developing new antibiotics has arisen because of the increasing resistance of bacteria against conventional antibiotics. Anti-microbial peptides (AMPs) have a strong potential to be a new generation of antibiotic drugs. Experimental studies show that the structure of peptide, the type of amino acid residues, and the membrane structure play a crucial role in the performance of AMPs. Most studies have stated that helical formation of AMPs on a bacterial membrane is the main reason for membrane disruption. LM7-1 and LM7-2 are two AMPs that were designed (Ryder and Martin, URI Cell and Molecular Biology) using combinations of naturally occurring AMPs. The difference between these two peptides is the 15th residue that differs from glycine in LM7-1 to lysine in LM7-2. This slight difference in the sequence of these two peptides has a significant effect on their performance and activities against bacteria. Ryder and Martin have proposed that different propensities of these two AMPs for helical structure on the membrane is the reason for their different performances. To study the effect of different amino acid residues on the stability of a helical structure of these two AMPs, molecular dynamics (MD) simulations were initiated using alpha helix structures of LM7-1 and LM7-2 in solution. By this study, the tendency of each AMP to remain in an alpha helix structure and the unfolding helix-to-coil process were investigated over MD simulations. In addition, MD simulations are being conducted on the system of a coil structure of AMP in a water-membrane environment to investigate the propensity of each AMP to be in a helical structure on the membrane. The large-scale motions of peptides result from small- amplitude fluctuations of atoms in the molecule. Hence, it is also worthy to study the inherent vibrations of atoms to specify vibrational modes that lead a peptide to be unfolded or folded. To address this issue, all-atom Normal Mode Analysis (NMA) was applied on the configuration results of MD simulations. NMA provides the vibrational frequencies and vibrational vectors of each frequency. Comparing analysis for both LM7-1 and LM7-2 demonstrates how one difference in the peptide sequence affects their propensity to be in a helical structure, and consequently has an effect on the functionality of AMPs in a water-membrane environment.