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Native protein sequences are close to optimal for their structures.

B Kuhlman1, D Baker

  • 1Department of Biochemistry and Howard Hughes Medical Institute, University of Washington School of Medicine, Seattle, WA 98195, USA.

Proceedings of the National Academy of Sciences of the United States of America
|September 14, 2000
PubMed
Summary
This summary is machine-generated.

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The study found that the range of amino acid sequences compatible with a protein structure is surprisingly small. Optimal sequences are closely related to the native sequence, suggesting limited evolutionary flexibility for protein structures.

Area of Science:

  • Protein structure and sequence analysis
  • Computational biology and biophysics

Background:

  • Understanding the relationship between protein structure and amino acid sequence is fundamental to molecular biology.
  • The vastness of possible protein sequences raises questions about the constraints imposed by a specific structure.

Purpose of the Study:

  • To determine the volume of sequence space compatible with a given protein structure.
  • To investigate if optimal sequences for a protein structure are confined to a narrow region around the native sequence.

Main Methods:

  • Generated low free energy sequences for 108 protein backbone structures using Monte Carlo optimization.
  • Employed a free energy function based on Lennard-Jones packing and implicit solvation models.
  • Analyzed sequence identity and residue frequencies/covariances in designed sequences compared to native sequences.

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Main Results:

  • Designed sequences showed high identity with native sequences (51% core, 27% all residues).
  • Lowest free energy sequences for native-like structures closely matched the native sequence.
  • Designed core sequences for SH3 domains recapitulated native residue frequencies and covariances.

Conclusions:

  • The sequence space compatible with a protein structure is unexpectedly restricted.
  • Optimal sequences are concentrated around the native sequence, implying limited evolutionary pathways for protein adaptation.