Abstract:
:We present a simple theory that uses thermodynamic parameters to predict the probability that a protein retains the wild-type 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.
journal_name
Proc Natl Acad Sci U S Aauthors
Bloom JD,Silberg JJ,Wilke CO,Drummond DA,Adami C,Arnold FHdoi
10.1073/pnas.0406744102keywords:
subject
Has Abstractpub_date
2005-01-18 00:00:00pages
606-11issue
3eissn
0027-8424issn
1091-6490pii
0406744102journal_volume
102pub_type
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