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Published January 19, 2001 | public
Journal Article

Achieving stability and conformational specificity in designed proteins via binary patterning


We have developed a method to determine the optimal binary pattern (arrangement of hydrophobic and polar amino acids) of a target protein fold prior to amino acid sequence selection in protein design studies. A solvent accessible surface is generated for a target fold using its backbone coordinates and "generic" side-chains, which are constructs whose size and shape are similar to an average amino acid. Each position is classified as hydrophobic or polar according to the solvent exposure of its generic side-chain. The method was tested by analyzing a set of proteins in the Protein Data Bank and by experimentally constructing and analyzing a set of engrailed homeodomain variants whose binary patterns were systematically varied. Selection of the optimal binary pattern results in a designed protein that is monomeric, well-folded, and hyperthermophilic. Homeodomain variants with fewer hydrophobic residues are destabilized, while additional hydrophobic residues induce aggregation. Binary patterning, in conjunction with a force field that models folded state energies, appears sufficient to satisfy two basic goals of protein design: stability and conformational specificity.

Additional Information

© 2001 Academic Press. Received 18 August 2000; revised 13 November 2000; Accepted 13 November 2000. Available online 26 February 2002. This work was supported by the Howard Hughes Medical Institute (S.L.M.), the National Institutes of Health, and the Caltech Initiative in Computational Molecular Biology, which is funded by a Burroughs Wellcome Fund Interfaces Award (S.A.M.).

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