Integrated solid-state NMR and molecular dynamics modeling determines membrane insertion of human β-defensin analog
© 2019, The Author(s). Human β-defensins (hBD) play central roles in antimicrobial activities against various microorganisms and in immune-regulation. These peptides perturb phospholipid membranes for function, but it is not well understood how defensins approach, insert and finally disrupt membranes on the molecular level. Here we show that hBD-3 analogs interact with lipid bilayers through a conserved surface that is formed by two adjacent loops in the solution structure. By integrating a collection of 13C, 1H and 31P solid-state NMR methods with long-term molecular dynamic simulations, we reveal that membrane-binding rigidifies the peptide, enhances structural polymorphism, and promotes β-strand conformation. The peptide colocalizes with negatively charged lipids, confines the headgroup motion, and deforms membrane into smaller, ellipsoidal vesicles. This study designates the residue-specific, membrane-bound topology of hBD-3 analogs, serves as the basis for further elucidating the function-relevant structure and dynamics of other defensins, and facilitates the development of defensin-mimetic antibiotics, antifungals, and anti-inflammatories.
Publication Source (Journal or Book title)
Kang, X., Elson, C., Penfield, J., Kirui, A., Chen, A., Zhang, L., & Wang, T. (2019). Integrated solid-state NMR and molecular dynamics modeling determines membrane insertion of human β-defensin analog. Communications Biology, 2 (1) https://doi.org/10.1038/s42003-019-0653-6