Journal
BIOCHEMISTRY
Volume 49, Issue 11, Pages 2307-2316Publisher
AMER CHEMICAL SOC
DOI: 10.1021/bi902077d
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Funding
- NIH [1-DP2-OD006478-01]
- NSF [DMR-0907273, MCB-0920448, MCB-5G12RR03060, P41 GM-66354]
- National Center for Research Resources [NIH 5G12 RR03060]
- Direct For Biological Sciences
- Div Of Molecular and Cellular Bioscience [0920448] Funding Source: National Science Foundation
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We sought to computationally design model collagen peptides that specifically associate as heterotrimers. Computational design has been successfully applied to the creation of new protein folds and functions. Despite the high abundance of collagen and its key role in numerous biological processes, fibrous proteins have received little attention as computational design targets. Collagens are composed of three polypeptide chains that wind into triple helices. We developed a discrete computational model to design heterotrimer-forming collagen-like peptides. Stability and specificity of oligomerization were concurrently targeted Using a combined positive and negative design approach. The sequences of three 30-residue peptides, A, B, and C, were optimized to favor charge-pair interactions in an ABC heterotrimer, while disfavoring the 26 competing oligomers (i.e., AAA, ABB, BCA). Peptides were synthesized and characterized for thermal stability and triple-helical structure by circular dichroism and NMR. A unique A:B:C-type species was not achieved. Negative design was partially successful, with only A + B and B + C competing mixtures formed. Analysis of computed versus experimental stabilities helps to clarify the role of electrostatics and secondary-structure propensities determining collagen stability and to provide Important insight Into how subsequent designs can be improved.
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