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Assess the thermodynamic stability costs of function-altering mutations relative to background mutations and determine how proteins balance these tradeoffs during directed evolution.

February 28, 2008SHILAP Revista de lepidopterologíaOpen Access

How Protein Stability and New Functions Trade Off

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Assess the thermodynamic stability costs of function-altering mutations relative to background mutations and determine how proteins balance these tradeoffs during directed evolution.
Applied FoldX to compute changes in thermodynamic stability (DeltaDeltaG) for 548 mutations generated across 22 enzymes during directed evolution.
Compared the stability impact, location, and mutation type of function-altering residues to all possible point mutations across the same enzymes.
Function-modulating mutations are predominantly destabilizing, with an average DeltaDeltaG of +0.9 kcal/mol compared to +1.3 kcal/mol for the average mutation in these enzymes.
Mutations modifying substrate binding pockets impose a higher stability penalty than surface neutral mutations, though less severe than changes to key catalytic residues.
Secondary mutations appearing without direct functional roles exert compensatory stabilizing effects that balance the destabilizing consequences of function-altering mutations.

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Implication

Computational analysis reveals function-altering mutations destabilize enzymes while secondary mutations restore stability, indicating that compensatory changes enable functional evolution.

Cite This Study

Tokuriki et al. (2008) studied this question.

synapsesocial.com/papers/69d6cb3e3cb98036e7ab3312 https://doi.org/10.1371/journal.pcbi.1000002

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Implication

Computational analysis reveals function-altering mutations destabilize enzymes while secondary mutations restore stability, indicating that compensatory changes enable functional evolution.

How Protein Stability and New Functions Trade Off

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Implication

Cite This Study

How Protein Stability and New Functions Trade Off

Key Points

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Implication

Cite This Study

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