Mathematical Techniques for Efficient Record Segmentation in Large Shared Databases
Journal of the ACM (JACM)
Parametric Combinatorial Computing and a Problem of Program Module Distribution
Journal of the ACM (JACM)
Graphical Models of Residue Coupling in Protein Families
IEEE/ACM Transactions on Computational Biology and Bioinformatics (TCBB)
RECOMB'06 Proceedings of the 10th annual international conference on Research in Computational Molecular Biology
Protein Fragment Swapping: A Method for Asymmetric, Selective Site-Directed Recombination
RECOMB 2'09 Proceedings of the 13th Annual International Conference on Research in Computational Molecular Biology
Protein Design by Sampling an Undirected Graphical Model of Residue Constraints
IEEE/ACM Transactions on Computational Biology and Bioinformatics (TCBB)
Optimization of combinatorial mutagenesis
RECOMB'11 Proceedings of the 15th Annual international conference on Research in computational molecular biology
Algorithms for optimizing cross-overs in DNA shuffling
Proceedings of the 2nd ACM Conference on Bioinformatics, Computational Biology and Biomedicine
Structure-Guided deimmunization of therapeutic proteins
RECOMB'12 Proceedings of the 16th Annual international conference on Research in Computational Molecular Biology
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In engineering protein variants by constructing and screening combinatorial libraries of chimeric proteins, two complementary and competing goals are desired: the new proteins must be similar enough to the evolutionarily-selected wild-type proteins to be stably folded, and they must be different enough to display functional variation. We present here the first method, Staversity, to simultaneously optimize stability and diversity in selecting sets of breakpoint locations for site-directed recombination. Our goal is to uncover all "undominated" breakpoint sets, for which no other breakpoint set is better in both factors. Our first algorithm finds the undominated sets serving as the vertices of the lower envelope of the two-dimensional (stability and diversity) convex hull containing all possible breakpoint sets. Our second algorithm identifies additional breakpoint sets in the concavities that are either undominated or dominated only by undiscovered breakpoint sets within a distance bound computed by the algorithm. Both algorithms are efficient, requiring only time polynomial in the numbers of residues and breakpoints, while characterizing a space defined by an exponential number of possible breakpoint sets. We applied Staversity to identify 2-10 breakpoint sets for three different sets of parent proteins from the purE family of biosynthetic enzymes. The average normalized distance between our plans and the lower bound for optimal plans is around 1 percent. Our plans dominate most (60-90% on average for each parent set) of the plans found by other possible approaches, random sampling or explicit optimization for stability with implicit optimization for diversity. The identified breakpoint sets provide a compact representation of good plans, enabling a protein engineer to understand and account for the trade-offs between two key considerations in combinatorial chimeragenesis.