Towards Full-Sequence De Novo Protein Design with
Flexible Templates for Human Beta-Defensin-2
Ho Ki Fung 1, Christodoulos A Floudas 1*, Martin S. Taylor 2, Li Zhang 3 and Dimitrios Morikis 4
1 Princeton University
2 Johns Hopkins University
3 University of California, Riverside
4 University of California at Riverside
* To whom correspondence should be addressed. E-mail: floudas{at}titan.princeton.edu.
Submitted on April 12, 2007
Revised on August 9, 2007
Accepted on 21 August 2007
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Abstract |
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In this paper we introduce and apply our de novo protein design framework, which observes true backbone flexibility (1), 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 demonstated with the full-sequence design of the peptide with flexible backbone templates, corresponding to the mutation of all positions except the native cysteines.
Key Words:
de novo protein design, drug design, global optimization, in silico sequence selection, peptide and protein design and discovery, structure prediction
