Editing Protein design (section)

===Enzyme design===

The design of new [[enzyme]]s is a use of protein design with huge bioengineering and biomedical applications. In general, designing a protein structure can be different from designing an enzyme, because the design of enzymes must consider many states involved in the [[enzyme catalysis|catalytic mechanism]]. However protein design is a prerequisite of ''de novo'' enzyme design because, at the very least, the design of catalysts requires a scaffold in which the catalytic mechanism can be inserted.<ref name="baker10">{{cite journal|last=Baker|first=D|title=An exciting but challenging road ahead for computational enzyme design.|journal=Protein Science|date=October 2010|volume=19|issue=10|pages=1817–9|pmid=20717908|doi=10.1002/pro.481|pmc=2998717}}</ref>

Great progress in ''de novo'' enzyme design, and redesign, was made in the first decade of the 21st century. In three major studies, David Baker and coworkers ''de novo'' designed enzymes for the retro-[[aldol reaction]],<ref name="jiang08">{{cite journal |doi=10.1126/science.1152692 |title=De Novo Computational Design of Retro-Aldol Enzymes |year=2008 |last1=Jiang |first1=Lin |last2=Althoff |first2=Eric A. |last3=Clemente |first3=Fernando R. |last4=Doyle |first4=Lindsey |last5=Rothlisberger |first5=Daniela |last6=Zanghellini |first6=Alexandre |last7=Gallaher |first7=Jasmine L. |last8=Betker |first8=Jamie L. |last9=Tanaka |first9=Fujie |journal=Science |volume=319 |pages=1387–91 |pmid=18323453 |issue=5868|bibcode= 2008Sci...319.1387J |pmc=3431203}}</ref> a Kemp-elimination reaction,<ref name="roth08">{{cite journal |doi=10.1038/nature06879 |title=Kemp elimination catalysts by computational enzyme design |year=2008 |last1=Röthlisberger |first1=Daniela |last2=Khersonsky |first2=Olga |last3=Wollacott |first3=Andrew M. |last4=Jiang |first4=Lin |last5=Dechancie |first5=Jason |last6=Betker |first6=Jamie |last7=Gallaher |first7=Jasmine L. |last8=Althoff |first8=Eric A. |last9=Zanghellini |first9=Alexandre |journal=Nature |volume=453 |pages=190–5 |pmid=18354394 |issue=7192|bibcode= 2008Natur.453..190R|doi-access=free }}</ref> and for the [[Diels-Alder reaction]].<ref>{{cite journal|last=Siegel|first=JB|author2=Zanghellini, A; Lovick, HM; Kiss, G; Lambert, AR; St Clair, JL; Gallaher, JL; Hilvert, D; Gelb, MH; Stoddard, BL; Houk, KN; Michael, FE; Baker, D|title=Computational design of an enzyme catalyst for a stereoselective bimolecular Diels-Alder reaction.|journal=Science|date=July 16, 2010|volume=329|issue=5989|pages=309–13|pmid=20647463|bibcode= 2010Sci...329..309S |doi= 10.1126/science.1190239|pmc=3241958}}</ref> Furthermore, Stephen Mayo and coworkers developed an iterative method to design the most efficient known enzyme for the Kemp-elimination reaction.<ref>{{cite journal|last=Privett|first=HK|author2=Kiss, G |author3=Lee, TM |author4=Blomberg, R |author5=Chica, RA |author6=Thomas, LM |author7=Hilvert, D |author8=Houk, KN |author9= Mayo, SL |title=Iterative approach to computational enzyme design.|journal=Proceedings of the National Academy of Sciences of the United States of America|date=March 6, 2012|volume=109|issue=10|pages=3790–5|pmid=22357762|bibcode= 2012PNAS..109.3790P |doi= 10.1073/pnas.1118082108 |pmc=3309769|doi-access=free}}</ref> Also, in the laboratory of [[Bruce Donald]], computational protein design was used to switch the specificity of one of the [[protein domain]]s of the [[nonribosomal peptide|nonribosomal peptide synthetase]] that produces [[Gramicidin S]], from its natural substrate [[Phenylalanine|phe]]nylalanine to other noncognate substrates including charged amino acids; the redesigned enzymes had activities close to those of the wild-type.<ref name="chen09">{{cite journal|last=Chen|first=CY|author2=Georgiev, I |author3=Anderson, AC |author4= Donald, BR |title=Computational structure-based redesign of enzyme activity.|journal=Proceedings of the National Academy of Sciences of the United States of America|date=March 10, 2009|volume=106|issue=10|pages=3764–9|pmid=19228942|bibcode= 2009PNAS..106.3764C |doi= 10.1073/pnas.0900266106 |pmc=2645347|doi-access=free}}</ref>