Dartmouth logo Dartmouth College Computer Science
Technical Report series
CS home
TR home
TR search TR listserv
By author: A B C D E F G H I J K L M N O P Q R S T U V W X Y Z
By number: 2017, 2016, 2015, 2014, 2013, 2012, 2011, 2010, 2009, 2008, 2007, 2006, 2005, 2004, 2003, 2002, 2001, 2000, 1999, 1998, 1997, 1996, 1995, 1994, 1993, 1992, 1991, 1990, 1989, 1988, 1987, 1986

Optimization Algorithms for Site-directed Protein Recombination Experiment Planning
Wei Zheng
Dartmouth TR2010-672

Abstract: Site-directed protein recombination produces improved and novel protein variants by recombining sequence fragments from parent proteins. The resulting hybrids accumulate multiple mutations that have been evolutionarily accepted together. Subsequent screening or selection identifies hybrids with desirable characteristics. In order to increase the "hit rate" of good variants, this thesis develops experiment planning algorithms to optimize protein recombination experiments. First, to improve the frequency of generating novel hybrids, a metric is developed to assess the diversity among hybrids and parent proteins. Dynamic programming algorithms are then created to optimize the selection of breakpoint locations according to this metric. Second, the trade-off between diversity and stability in recombination experiment planning is studied, recognizing that diversity requires changes from parent proteins, which may also disrupt important residue interactions necessary for protein stability. Accordingly, methods based on dynamic programming are developed to provide combined optimization of diversity and stability, finding optimal breakpoints such that no other experiment plan has better performance in both aspects simultaneously. Third, in order to support protein recombination with heterogeneous structures and focus on functionally important regions, a general framework for protein fragment swapping is developed. Differentiating source and target parents, and swappable regions within them, fragment swapping enables asymmetric, selective site-directed recombination. Two applications of protein fragment swapping are studied. In order to generate hybrids inheriting functionalities from both source and target proteins by fragment swapping, a method based on integer programming selects optimal swapping fragments to maximize the predicted stability and activity of hybrids in the resulting library. In another application, human source protein fragments are swapped into therapeutic exogenous target protein to minimize the occurrence of peptides that trigger immune response. A dynamic programming method is developed to optimize fragment selection for both humanity and functionality, resulting in therapeutically active variants with decreased immunogenicity.

Note: Ph.D Dissertation of Wei Zheng in Computer Science at Dartmouth College. Advisor: Chris Bailey-Kellogg

PDF PDF (7000KB)

Bibliographic citation for this report: [plain text] [BIB] [BibTeX] [Refer]

Or copy and paste:
   Wei Zheng, "Optimization Algorithms for Site-directed Protein Recombination Experiment Planning." Dartmouth Computer Science Technical Report TR2010-672, June 2010.

Notify me about new tech reports.

Search the technical reports.

To receive paper copy of a report, by mail, send your address and the TR number to reports AT cs.dartmouth.edu

Copyright notice: The documents contained in this server are included by the contributing authors as a means to ensure timely dissemination of scholarly and technical work on a non-commercial basis. Copyright and all rights therein are maintained by the authors or by other copyright holders, notwithstanding that they have offered their works here electronically. It is understood that all persons copying this information will adhere to the terms and constraints invoked by each author's copyright. These works may not be reposted without the explicit permission of the copyright holder.

Technical reports collection maintained by David Kotz.