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Optimization of Synthetic Proteins: Identification of Interpositional Dependencies Indicating Structurally and/or Functionally Linked Residues
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Mutational effects on stability are largely conserved during protein evolution.

Orr Ashenberg1, L Ian Gong, Jesse D Bloom

  • 1Division of Basic Sciences and Computational Biology Program, Fred Hutchinson Cancer Research Center, Seattle, WA 98109.

Proceedings of the National Academy of Sciences of the United States of America
|December 11, 2013
PubMed
Summary
This summary is machine-generated.

Phylogenetic analyses often assume independent protein sites, but this study shows mutational effects on protein stability are largely conserved across homologs. Large evolutionary shifts in these effects are rare, suggesting focus on individual site preferences is key.

Keywords:
consensus designheterotachysubstitution models

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Area of Science:

  • Biochemistry
  • Evolutionary Biology
  • Structural Biology

Background:

  • Protein stability and folding rely on complex residue interactions.
  • Phylogenetic methods often simplify this by assuming site independence.
  • This simplification raises concerns about evolutionary shifts in mutational effects.

Purpose of the Study:

  • To experimentally test if mutational effects on protein stability are conserved across protein homologs.
  • To investigate potential confounding effects of evolutionary shifts in mutational impacts on phylogenetic analyses.

Main Methods:

  • Introducing identical mutations into diverged influenza nucleoprotein homologs.
  • Measuring the impact of these mutations on protein stability.
  • Simulating protein evolution using molecular-mechanics force fields.

Main Results:

  • Mutational effects on protein stability were found to be largely conserved across homologs.
  • Simulations supported the experimental findings of conserved mutational effects.
  • Large evolutionary shifts in mutational effects on stability appear to be infrequent.

Conclusions:

  • Conserved mutational effects on stability suggest phylogenetic approaches focusing on individual site preferences are robust.
  • Epistasis can still occur even with conserved mutational effects.
  • Rare shifts in amino acid propensities due to site covariation are less critical for phylogenetic analyses than conserved site preferences.