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'''Structure-based combinatorial protein engineering''' ('''SCOPE''') is a [[synthetic biology]] technique for creating [[gene library|gene libraries]] ([[lineage (evolution)|lineages]]) of defined composition designed from structural and probabilistic constraints of the encoded proteins. The development of this technique was driven by fundamental questions about [[protein structure]], [[Protein#Cellular functions|function]], and evolution, although the technique is generally applicable for the creation of engineered proteins with commercially desirable properties. Combinatorial travel through sequence [[spacetime]] is the goal of SCOPE.{{citation needed|date=February 2016}}

==Description==
At its inception, SCOPE was developed as a [[homology (biology)|homology]]-independent recombination technique to enable the creation of multiple crossover libraries from distantly related genes. In this application, an “exon [[plate tectonics]]” design strategy was devised to assemble “equivalent” elements of structure ([[continental plates]]) with variability in the junctions linking them ([[fault (geology)|fault lines]]) to explore global protein space. To create the corresponding library of genes, the breeding scheme of [[Gregor Mendel]] was adapted into a [[Polymerase chain reaction|PCR]] strategy to selectively cross hybrid genes, a process of [[Iteration|iterative]] inbreeding to create all possible combinations of coding segments with variable linkages. [[Complementation (genetics)|Genetic complementation]] in temperature-sensitive [[Escherichia coli|E. coli]] was used as the selection system to successfully identify functional [[hybrid (biology)|hybrid]] [[DNA polymerases]] of minimal architecture with enhanced [[phenotype]]s.

SCOPE was then used to construct a synthetic [[enzyme]] lineage, which was biochemically characterized to recapitulate the evolutionary divergence of two modern day enzymes. The rapid evolvability of chemical diversity in [[terpene]] [[synthase]]s were demonstrated through processes akin to both Darwinian [[gradualism]] and [[saltation (biology)|saltation]]: some mutational pathways show steady, additive changes, whereas others show drastic jumps between contrasting product specificities with single mutational steps. Further, a metric was devised to describe the chemical distance of mutational steps to derive a chemical-based [[Phylogenetics|phylogeny]] relating sequence variation to chemical output. These examples establish SCOPE as a standardized method for the construction of synthetic gene libraries from close or distantly related parental sequences to identify functional novelty among the encoded proteins.

== See also ==
* [[Directed evolution]]
* [[Enzymology]]
* [[Expanded genetic code]]
* [[Gene synthesis]]
* [[Genome]]
* [[Nucleic acid analogues]]
* [[Protein design]]
* [[Protein engineering]]
* [[Protein folding]]
* [[Proteomics]]
* [[Proteome]]
* [[Structural biology]]
* [[Synthetic biology]]

== Further reading ==
* {{cite journal | vauthors = O'Maille PE, Bakhtina M, Tsai MD | title = Structure-based combinatorial protein engineering (SCOPE) | journal = Journal of Molecular Biology | volume = 321 | issue = 4 | pages = 677–91 | date = Aug 2002 | pmid = 12206782 | doi = 10.1016/S0022-2836(02)00675-7 }}
* {{cite book | vauthors = O'Maille PE, Tsai MD, Greenhagen BT, Chappell J, Noel JP | title = Protein Engineering | chapter = Gene library synthesis by structure-based combinatorial protein engineering | series = Methods in Enzymology | volume = 388 | pages = 75–91 | year = 2004 | pmid = 15289063 | doi = 10.1016/S0076-6879(04)88008-X | isbn = 9780121827939 }}
* {{cite journal | vauthors = O'Maille PE, Malone A, Dellas N, Andes Hess B, Smentek L, Sheehan I, Greenhagen BT, Chappell J, Manning G, Noel JP | title = Quantitative exploration of the catalytic landscape separating divergent plant sesquiterpene synthases | journal = Nature Chemical Biology | volume = 4 | issue = 10 | pages = 617–23 | date = Oct 2008 | pmid = 18776889 | pmc = 2664519 | doi = 10.1038/nchembio.113 }}

== External links ==
* [http://www.wipo.int/pctdb/en/wo.jsp?wo=2005118861 SCOPE Patent]

[[Category:Combinatorial chemistry]]
[[Category:Evolutionary biology]]
[[Category:Protein engineering]]
[[Category:Synthetic biology| ]]

Structure-based combinatorial protein engineering - Revision history

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