Design of a heterospecific, tetrameric, 21-residue miniprotein with mixed alpha/beta structure.
The study of short, autonomously folding peptides, or "miniproteins," is important for advancing our understanding of protein stability and folding specificity. Although many examples of synthetic alpha-helical structures are known, relatively few mixed alpha/beta structures have been successfully designed. Only one mixed-secondary structure oligomer, an alpha/beta homotetramer, has been reported thus far. In this report, we use structural analysis and computational design to convert this homotetramer into the smallest known alpha/beta-heterotetramer. Computational screening of many possible sequence/structure combinations led efficiently to the design of short, 21-residue peptides that fold cooperatively and autonomously into a specific complex in solution. A 1.95 A crystal structure reveals how steric complementarity and charge patterning encode heterospecificity. The first- and second-generation heterotetrameric miniproteins described here will be useful as simple models for the analysis of protein-protein interaction specificity and as structural platforms for the further elaboration of folding and function.
Ali
Mayssam H
MH
Department of Chemistry, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA.
Taylor
Christina M
CM
Grigoryan
Gevorg
G
Allen
Karen N
KN
Imperiali
Barbara
B
Keating
Amy E
AE
D000595:Amino Acid Sequence; D019295:Computational Biology; D003460:Crystallization; D018360:Crystallography, X-Ray; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D010455:Peptides / Q000737:chemistry* / Q000235:genetics; D017510:Protein Folding; D017433:Protein Structure, Secondary
D010455:Peptides