The protein-folding problem: The native fold determines packing, but does packing determine the native fold?

Michael J. Behe, Eaton E. Lattman, George D. Rose

Research output: Contribution to journalArticlepeer-review

Abstract

A globular protein adopts its native three-dimensional structure spontaneously under physiological conditions. This structure is specified by a stereochemical code embedded within the amino acid sequence of that protein. Elucidation of this code is a major, unsolved challenge, known as the protein-folding problem. A critical aspect of the code is thought to involve molecular packing. Globular proteins have high packing densities, a consequence of the fact that residue side chains within the molecular interior fit together with an exquisite complementarity, like pieces of a three-dimensional jigsaw puzzle [Richards, F. M. (1977) Annu. Rev. Biophys. Bioeng. 6, 151]. Such packing interactions are widely viewed as the principal determinant of the native structure. To test this view, we analyzed proteins of known structure for the presence of preferred interactions, reasoning that if side-chain complementarity is an important source of structural specificity, then sets of residues that interact favorably should be apparent. Our analysis leads to the surprising conclusion that high packing densities - so characteristic of globular proteins - are readily attainable among clusters of the naturally occurring hydrophobic amino acid residues. It is anticipated that this realization will simplify approaches to the protein-folding problem.

Original languageEnglish (US)
Pages (from-to)4195-4199
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume88
Issue number10
DOIs
StatePublished - May 15 1991
Externally publishedYes

Keywords

  • Protein engineering
  • Protein packing

ASJC Scopus subject areas

  • General

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