Toward full-sequence de novo protein design with flexible templates for human beta-defensin-2

In this article, we introduce and apply our de novo protein design framework, which observes true backbone flexibility, to the redesign of human beta-defensin-2, a 41-residue cationic antimicrobial peptide of the innate immune system. The flexible design templates are generated using molecular dynamics simulations with both Generalized Born implicit solvation and explicit water molecules. These backbone templates were employed in addition to the x-ray crystal structure for designing human beta-defensin-2. The computational efficiency of our framework was demonstrated with the full-sequence design of the peptide with flexible backbone templates, corresponding to the mutation of all positions except the native cysteines.