Multi-Target Design and Analysis of DNA-Binding Antimicrobial Peptides

Wellesley College, Wellesley Hills MA

Investigators

Abstract

Antimicrobial peptides (AMPs) are a potentially promising strategy to address the ongoing health crisis of antibiotic-resistant microbial infection because they target generic bacterial structural elements, thereby rendering evolutionary pathways for bacterial resistance more difficult. Some AMPs have a hypothesized mechanism of action that first involves interacting with the bacterial cell membrane and translocating across it to enter the bacterial cell. Once these AMPs enter bacteria, they can interact with intracellular targets such as DNA. Interactions between these cationic peptides and both of their negatively-charged membrane and nucleic acid targets are mediated in large part by electrostatics. This project involves the design of AMPs with increased antimicrobial potency through rationally modifying five AMPs believed to target nucleic acids to achieve enhanced membrane and DNA binding affinity. The project workflow integrates computational techniques, such as optimization, molecular dynamics simulations, and continuum electrostatic modeling with experimental techniques, such as spectroscopy, microbiological testing, and vesicle-based assays. This multifaceted approach will allow for not only the engineering of potentially more active therapeutics but also the deeper understanding of multi-target molecular recognition in electrostatically-driven systems. Specifically, the research team will first design peptides with a range of affinities to each single target – either membrane or DNA – followed by studies to determine how binding affinity relates to antimicrobial potency and mechanism of action. Based on these results, they will then design and analyze peptides co-optimized to ideally interact promiscuously to both membrane and DNA targets. By comparing structural bases of designs resulting from different objectives, the research team will gain insight into the mechanisms of molecular recognition in this system. The project will also provide a rich cycle of computation and experiment that can be used to improve physically-based models and yield a design framework that can be applied to other peptide systems. In addition to these scientific goals, this work will focus on enhancing educational and training opportunities at Wellesley College, a women’s undergraduate-only institution. Through this research, Wellesley students will have the opportunity to take ownership of projects at the interface of computation and experiment.