J Chem Inf Model. 2026 Apr 30. doi: 10.1021/acs.jcim.5c02937. Online ahead of print.
ABSTRACT
Human β defensin type 3 (hBD-3) is recognized as one of the most intriguing antimicrobial peptides (AMPs) that holds the promise of solving drug resistance issues. hBD-3 can function (disruption of membrane integrity) in high salt environments, where most other AMPs fail. However, its functional mechanism at the molecular level remains elusive. To characterize its structure and dynamics during membrane crossing, long-time (a total of 57.0 μs) all-atom molecular dynamics simulations were conducted on hBD-3 monomers and dimers in both wild-type and analog (in which all three disulfide bonds are broken) forms that are embedded in four types of lipid membranes. Trajectory analysis was carried out using a statistical method─conformational dynamics analysis to calculate contact matrices and then principal component analysis (PCA) and linear discriminant analysis (LDA), in order to discern structural changes upon various physical and chemical perturbations. The result shows that the major collective coordinate primarily distinguishes between the wild-type and analog forms of hBD-3. For the hBD-3 monomer, the analog undergoes significant structural loss due to the lack of stabilizing disulfide bonds; salt exerts a nearly consistent effect on the contact degrees of freedom of the protein, whereas changes in lipid membrane composition have an insignificant effect. For the hBD-3 dimer, no consistent relationship between structure and salt concentration is indicated, and variations in the chemical composition of model bacterial membranes have a limited effect on its dynamics. These results suggest that the wild-type and analog forms of hBD-3 may employ different mechanisms when crossing bacterial membranes. The effect of salt on hBD-3 dynamics can be mitigated by the high net charge density of the protein. Additionally, the hBD-3 dimer can distinguish between model Gram-positive and Gram-negative membranes, whereas the monomer cannot. Overall, these findings provide unique insights into the structure, dynamics, and membrane-disrupting mechanism of hBD-3.
PMID:42060321 | DOI:10.1021/acs.jcim.5c02937
