Design of combinatorial protein libraries of optimal size

Manish C. Saraf, Anshuman Gupta, Costas D. Maranas

Research output: Contribution to journalArticlepeer-review

22 Scopus citations

Abstract

In this article we introduce a computational procedure, OPTCOMB (Optimal Pattern of Tiling for COMBinatorial library design), for designing protein hybrid libraries that optimally balance library size with quality. The proposed procedure is directly applicable to oligonucleotide ligation-based protocols such as GeneReassembly, DHR, SISDC, and many more. Given a set of parental sequences and the size ranges of the parental sequence fragments, OPTCOMB determines the optimal junction points (i.e., crossover positions) and the fragment contributing parental sequences at each one of the junction points. By rationally selecting the junction points and the contributing parental sequences, the number of clashes (i.e., unfavorable interactions) in the library is systematically minimized with the aim of improving the overall library quality. Using OPTCOMB, hybrid libraries containing fragments from three different dihydrofolate reductase sequences (Escherichia coli, Bacillus subtilis, and Lactobacillus casei) are computationally designed. Notably, we find that there exists an optimal library size when both the number of clashes between the fragments composing the library and the average number of clashes per hybrid in the library are minimized. Results reveal that the best library designs typically involve complex tiling patterns of parental segments of unequal size hard to infer without relying on computational means.

Original languageEnglish (US)
Pages (from-to)769-777
Number of pages9
JournalProteins: Structure, Function and Genetics
Volume60
Issue number4
DOIs
StatePublished - Sep 1 2005

All Science Journal Classification (ASJC) codes

  • Structural Biology
  • Biochemistry
  • Molecular Biology

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