Sukin (Hannah) Sim
Computational and Experimental Characterization of Histone-Derived Antimicrobial Peptide Nucleic Acid Binding
Due to the growing medical concern of drug resistance, there is a need to develop alternatives to conventional antibiotics. Antimicrobial peptides (AMPs), which are found in numerous living organisms, are active against a wide range of bacteria and other pathogens and therefore show potential as a class of antibiotic alternatives. While many AMPs inhibit bacterial growth through membrane disruption, certain AMPs, including buforin II and DesHDAP1, are hypothesized to kill bacteria by binding to nucleic acids inside the bacterial cell after translocating across cell membrane. To understand this lesser known mechanism, the nucleic acid-peptide binding interactions of these systems were investigated using both experimental and computational methods. The experimental side of the research showed that having an increased composition of basic residues that are arginine versus lysine promoted binding for both buforin II and DesHDAP1. When binding was compared for different nucleic acid sequences, neither buforin II nor DesHDAP1 significantly favored particular DNA or RNA sequences. To provide confirmation and in-depth structural explanations for these results, different computational methods involving molecular dynamics (MD) simulations and electrostatics calculations were used. Through these computational analyses, particular arginine residues within each peptide were found to interact more favorably with nucleic acids. These insights regarding nucleic acid binding of buforin II and DesHDAP1, paired with a deeper understanding of the peptides' structures and membrane interactions, are necessary for development of novel pharmaceutical applications using AMPs, which include serving as alternatives to conventional antibiotics as well as drug delivery and anti-cancer agents.