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J Mol Biol. 1999 Nov 12;293(5):1183-93.

De novo protein design. II. Plasticity in sequence space.

Author information

1
Department of Structural Biology, Fairchild Building, Stanford University, Stanford, CA 94305, USA. koehl@hyper.stanford.edu

Abstract

It is generally accepted that many different protein sequences have similar folded structures, and that there is a relatively high probability that a new sequence possesses a previously observed fold. An indirect consequence of this is that protein design should define the sequence space accessible to a given structure, rather than providing a single optimized sequence. We have recently developed a new approach for protein sequence design, which optimizes the complete sequence of a protein based on the knowledge of its backbone structure, its amino acid composition and a physical energy function including van der Waals interactions, electrostatics, and environment free energy. The specificity of the designed sequence for its template backbone is imposed by keeping the amino acid composition fixed. Here, we show that our procedure converges in sequence space, albeit not to the native sequence of the protein. We observe that while polar residues are well conserved in our designed sequences, non-polar amino acids at the surface of a protein are often replaced by polar residues. The designed sequences provide a multiple alignment of sequences that all adopt the same three-dimensional fold. This alignment is used to derive a profile matrix for chicken triose phosphate isomerase, TIM. The matrix is found to recognize significantly the native sequence for TIM, as well as closely related sequences. Possible application of this approach to protein fold recognition is discussed.

PMID:
10547294
DOI:
10.1006/jmbi.1999.3212
[Indexed for MEDLINE]

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