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Toward Full-Sequence De Novo Protein Design with Flexible Templates for Human Beta-Defensin-2

Ho Ki Fung ^*, Christodoulos A. Floudas ^*, Martin S. Taylor , Li Zhang  and Dimitrios Morikis 

^* Department of Chemical Engineering, Princeton University, Princeton, New Jersey; School of Medicine, The Johns Hopkins University, Baltimore, Maryland; and Department of Chemistry and Department of Bioengineering, University of California, Riverside, California

Correspondence: Address reprint requests to C. A. Floudas, Tel.: 609-258-4595; E-mail: floudas{at}titan.princeton.edu.

In this article, we introduce and apply our de novo protein design framework, which observes true backbone flexibility, to the redesign of human β-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 β-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.