  Short peptides with antimicrobial activity have therapeutic potential for
treating bacterial infections. Mechanisms of actions for antimicrobial peptides
require binding the biological membrane of their target, which often represents
a key mechanistic step. A multitude of data-driven approaches have been
developed to predict potential antimicrobial peptide sequences; however, these
methods are usually agnostic to the physical interactions between the peptide
and the membrane. Towards developing higher throughput screening methodologies,
here we use Markov State Modeling and all-atom molecular dynamics simulations
to quantify the membrane binding and insertion kinetics of three prototypical
and antimicrobial peptides (alpha-helical magainin 2 and PGLa and beta-hairpin
tachyplesin 1). By leveraging a set of collective variables that capture the
essential physics of the amphiphilic and cationic peptide-membrane interactions
we reveal how the slowest kinetic process of membrane insertion is the dynamic
rolling of the peptide from a prebound to fully inserted state. These results
add critical details to how antimicrobial peptides insert into bacterial
membranes.
