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Functional Sites Induce Long-Range Evolutionary Constraints in Enzymes.

Benjamin R Jack1, Austin G Meyer1, Julian Echave2

  • 1Department of Integrative Biology, Center for Computational Biology and Bioinformatics, and Institute for Cellular and Molecular Biology, The University of Texas at Austin, Austin, Texas, United States of America.

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Protein catalytic residues drive evolutionary conservation, with conservation decreasing linearly with distance. This long-range evolutionary constraint impacts most enzyme residues, independent of other structural factors.

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Area of Science:

  • Biochemistry
  • Evolutionary Biology
  • Structural Biology

Background:

  • Functional residues in proteins are typically highly conserved.
  • The extent to which functional sites influence evolutionary constraints on neighboring or distant residues is not well understood.

Purpose of the Study:

  • To investigate the long-range evolutionary constraints imposed by functional sites, particularly catalytic residues, in enzymes.
  • To determine if conservation gradients exist around functional sites and how they relate to distance.

Main Methods:

  • Analysis of evolutionary conservation patterns in a dataset of 524 distinct enzymes.
  • Quantification of conservation gradients relative to the distance from the nearest catalytic residue.
  • Comparison of conservation patterns around catalytic sites versus protein-protein interfaces.

Main Results:

  • A pervasive, approximately linear decrease in evolutionary conservation with increasing distance to the nearest catalytic residue was observed.
  • This conservation gradient affects approximately 80% of residues in an enzyme and is independent of residue packing or solvent accessibility.
  • The trend was consistent across monomeric and multimeric enzymes, regardless of size or active site location.
  • Protein-protein interface sites showed weaker conservation and induced only minor gradients compared to catalytic residues.

Conclusions:

  • Catalytic residues in enzymes impose significant long-range evolutionary constraints.
  • These constraints extend far beyond the immediate vicinity of the functional site, influencing a large proportion of the protein.
  • Functional sites, especially catalytic ones, are key drivers of evolutionary patterns in proteins.