Abstract

Antimicrobial peptides (AMPs) are part of the innate immune system of many species from plants to mammals, showing antimicrobial activity against a wide range of microorganisms. Aurein peptides are a family of AMPs isolated from amphibians, displaying antibacterial and anticancer activity. In this work, we study the structure and dynamics of a set of Aurein peptides in aqueous solution and micellar environment using atomistic molecular dynamics (MD) simulations. We study six Aurein peptides, four of which are experimentally known to have antibacterial and anticancer activity (Aureins 1.2, 2.2, 2.5, and 3.1); and two longer Aurein peptides (Aureins 4.1 and 5.1) that are inactive. We build Markov state models (MSMs) to investigate the conformations of the peptides and transitions between different folding intermediates. Aurein 1.2 is an experimentally well-characterized peptide; there is literature reporting on the structures of Aurein 2.2 and 2.5. Our data show that the active Aureins visit three conformational states in solution: alpha-helical, partially alpha-helical, and random coil. The inactive Aureins show rapid transitions between short-lived conformations, and their MSMs were not reproducible. The simulations of Aureins 1.2 and 2.5 in micelles has shown that these peptides retain their folded α-helical structure in a hydrophobic environment. The secondary amide proton chemical shifts of Aurein 1.2 in micelle environments differing in the number of detergent molecules were computed and compared to the available experimental data. The micelle simulations comprising 80 SDS molecules agree well with the experimental data, suggesting that our simulations can predict the folding of Aurein peptides in micelles. Our results show that combining molecular simulations with MSMs enables the prediction of in-micelle conformations for Aurein peptides lacking experimental structures.