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Computationally Optimizing the Directed Evolution of Proteins


Voigt, Christopher Ashby (2003) Computationally Optimizing the Directed Evolution of Proteins. Dissertation (Ph.D.), California Institute of Technology. doi:10.7907/E4GF-EQ41.


Directed evolution has proven a successful strategy for protein engineering. To accelerate the discovery process, we have developed several computational methods to optimize the mutant libraries by targeting specific residues for mutagenesis, and subunits for recombination. In achieving this goal, a statistical model was first used to study the dynamics of directed evolution as a search algorithm. These simulations improved our understanding of the relationship between parameters describing the search space (e.g., interactions between amino acids) and experimental search parameters (e.g., mutation rate and library size). Based on these simulations, a more detailed model was used to calculate the structural tolerance of each residue to amino acid substitutions. Further, a computational model was developed to optimize recombination experiments, based on the three-dimensional structure. Together, these computational techniques represent a major step towards information-driven combinatorial protein design.

Item Type:Thesis (Dissertation (Ph.D.))
Subject Keywords:directed evolution; enzyme; genetic algorithm; library; mutagenesis; protein; recombination; schema
Degree Grantor:California Institute of Technology
Major Option:Biochemistry and Molecular Biophysics
Thesis Availability:Public (worldwide access)
Research Advisor(s):
  • Wang, Zhen-Gang (advisor)
  • Arnold, Frances Hamilton (co-advisor)
  • Mayo, Stephen L. (co-advisor)
Thesis Committee:
  • Rees, Douglas C. (chair)
  • Arnold, Frances Hamilton
  • Roberts, Richard W.
  • Mayo, Stephen L.
  • Fontana, Walter
  • Wang, Zhen-Gang
Defense Date:25 July 2002
Record Number:CaltechETD:etd-08192002-161141
Persistent URL:
Voigt, Christopher Ashby0000-0003-0844-4776
Default Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:3169
Deposited By: Imported from ETD-db
Deposited On:04 Sep 2002
Last Modified:08 Nov 2023 00:11

Thesis Files

PDF (voigt_thesis.pdf) - Final Version
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