(677a) Highlight: Multiscale Models of Antimicrobial Peptides

Antimicrobial peptides (AMPs) are naturally-occurring molecules that exhibit strong antibiotic properties against numerous infectious bacterial strains.
Because of their unique mechanism of action, they have been touted as a potential source for novel antibiotic drugs.

We will present a summary of computational investigations from the past five years aimed at understanding
this unique mechanism of action. In particular, we stress the development of models that provide a quantitative connection between molecular-level
biophysical phenomena and relevant biological effects. Our work is focused on protegrins, a potent class of AMPs that attack bacteria by associating
with the bacterial membrane and forming transmembrane pores that facilitate the unrestricted transport of ions. Using fully atomistic molecular dynamics
simulations, we have computed the thermodynamics of peptide-membrane association and insertion, as well as peptide aggregation. Based on the
resulting molecular-level free energy profiles, we have developed models that allow us to predict macroscopically relevant quantities such as
membrane adsorption and insertion isotherms. Earlier work in our group employed molecular simulations to study the structure of protegrin pores in
great detail, which was also the first fully atomistic simulation study of any AMP pore structure. Based on this molecular information, we subsequently
carried out a thorough multi-scale analysis of the ion transport properties of protegrin pores, ranging from mesoscale continuum models of single-pore
electrodiffusion to models of transient ion transport from bacterial cells.

Overall, our work provides a quantitative mechanistic description of the mechanism of action of protegrin antimicrobial peptides across multiple
length and time scales.