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