dorsal/arxiv
View SchemaThermodynamic Prediction of Protein Neutrality
| Authors | Jesse D. Bloom, Jonathan J. Silberg, Claus O. Wilke, D. Allan Drummond, Christoph Adami, Frances H. Arnold |
|---|---|
| Categories | |
| ArXiv ID | q-bio/0409013 |
| URL | https://arxiv.org/abs/q-bio/0409013 |
| DOI | 10.1073/pnas.0406744102 |
| Journal | Proc. Natl. Acad. Sci. USA, 102:606-611, 2005 |
Abstract
We present a simple theory that uses thermodynamic parameters to predict the probability that a protein retains the wildtype structure after one or more random amino acid substitutions. Our theory predicts that for large numbers of substitutions the probability that a protein retains its structure will decline exponentially with the number of substitutions, with the severity of this decline determined by properties of the structure. Our theory also predicts that a protein can gain extra robustness to the first few substitutions by increasing its thermodynamic stability. We validate our theory with simulations on lattice protein models and by showing that it quantitatively predicts previously published experimental measurements on subtilisin and our own measurements on variants of TEM1 beta-lactamase. Our work unifies observations about the clustering of functional proteins in sequence space, and provides a basis for interpreting the response of proteins to substitutions in protein engineering applications.
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"abstract": "We present a simple theory that uses thermodynamic parameters to predict the\nprobability that a protein retains the wildtype structure after one or more\nrandom amino acid substitutions. Our theory predicts that for large numbers of\nsubstitutions the probability that a protein retains its structure will decline\nexponentially with the number of substitutions, with the severity of this\ndecline determined by properties of the structure. Our theory also predicts\nthat a protein can gain extra robustness to the first few substitutions by\nincreasing its thermodynamic stability. We validate our theory with simulations\non lattice protein models and by showing that it quantitatively predicts\npreviously published experimental measurements on subtilisin and our own\nmeasurements on variants of TEM1 beta-lactamase. Our work unifies observations\nabout the clustering of functional proteins in sequence space, and provides a\nbasis for interpreting the response of proteins to substitutions in protein\nengineering applications.",
"arxiv_id": "q-bio/0409013",
"authors": [
"Jesse D. Bloom",
"Jonathan J. Silberg",
"Claus O. Wilke",
"D. Allan Drummond",
"Christoph Adami",
"Frances H. Arnold"
],
"categories": [
"q-bio.BM",
"q-bio.PE"
],
"doi": "10.1073/pnas.0406744102",
"journal_ref": "Proc. Natl. Acad. Sci. USA, 102:606-611, 2005",
"title": "Thermodynamic Prediction of Protein Neutrality",
"url": "https://arxiv.org/abs/q-bio/0409013"
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