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How structural and physicochemical determinants shape sequence constraints in a functional enzyme.

Luciano A Abriata1, Timothy Palzkill2, Matteo Dal Peraro1

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Summary
This summary is machine-generated.

Protein evolution is shaped by physics and chemistry, with residue substitutions near the active site being highly restricted. This study quantifies sequence-trait relationships, revealing constraints on protein design and function.

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Area of Science:

  • Structural Biology
  • Biophysics
  • Molecular Evolution

Background:

  • Understanding how physical and chemical principles govern protein sequence space is crucial for molecular evolution.
  • Functional proteins must balance evolutionary possibilities with biological requirements.

Purpose of the Study:

  • To quantitatively analyze all possible amino acid substitutions in a functional enzyme (TEM lactamase).
  • To investigate the structure-based constraints on protein sequence space and their relationship to evolutionary processes.

Main Methods:

  • Utilized a high-resolution map of substitution tolerance derived from deep sequencing of TEM lactamase mutants.
  • Employed quantitative, structure-based analysis correlating amino acid properties with substitution patterns.
  • Modeled substitution patterns using amino acid descriptors and predicted changes in folding stability.

Main Results:

  • Substitutions are highly restricted within 7 Å of the enzyme's active site, with tolerance increasing gradually up to 15-20 Å.
  • Buried residues exhibit particular sensitivity to substitutions.
  • Over one-third of residue substitution patterns can be modeled by amino acid properties like volume, hydrophobicity, solubility, and charge, influencing protein core, surface, and stability.
  • Identified specific physicochemical properties (e.g., volume, hydrophobicity, solubility, charge) that dictate constraints on protein structure and function.

Conclusions:

  • Physicochemical properties fundamentally shape protein evolution and design by defining sequence-trait relationships.
  • Revealed subtle and unexpected links between amino acid sequences and protein traits.
  • Demonstrated how specific traits are compromised during gain-of-function mutations, offering insights into evolutionary trade-offs.