Editing Protein design (section)

===Design for specificity ===

The design of protein–protein interactions must be highly specific because proteins can interact with a large number of proteins; successful design requires selective binders. Thus, protein design algorithms must be able to distinguish between on-target (or ''positive design'') and off-target binding (or ''negative design'').<ref name="richardson1989"/><ref name=kuhlman2009 /> One of the most prominent examples of design for specificity is the design of specific [[bZIP domain|bZIP]]-binding peptides by Amy Keating and coworkers for 19 out of the 20 bZIP families; 8 of these peptides were specific for their intended partner over competing peptides.<ref name="kuhlman2009" /><ref name="schreiber11">{{cite journal|last=Schreiber|first=G|author2=Keating, AE |title=Protein binding specificity versus promiscuity.|journal=Current Opinion in Structural Biology|date=February 2011|volume=21|issue=1|pages=50–61|pmid=21071205|doi=10.1016/j.sbi.2010.10.002|pmc=3053118}}</ref><ref>{{cite journal|last=Grigoryan|first=G|author2=Reinke, AW |author3=Keating, AE |title=Design of protein-interaction specificity gives selective bZIP-binding peptides.|journal=Nature|date=April 16, 2009|volume=458|issue=7240|pages=859–64|pmid=19370028|bibcode= 2009Natur.458..859G |doi= 10.1038/nature07885 |pmc=2748673}}</ref> Further, positive and negative design was also used by Anderson and coworkers to predict mutations in the active site of a drug target that conferred resistance to a new drug; positive design was used to maintain wild-type activity, while negative design was used to disrupt binding of the drug.<ref name="frey10">{{cite journal|last=Frey|first=KM|author2=Georgiev, I |author3=Donald, BR |author4= Anderson, AC |title=Predicting resistance mutations using protein design algorithms.|journal=Proceedings of the National Academy of Sciences of the United States of America|date=August 3, 2010|volume=107|issue=31|pages=13707–12|pmid=20643959|bibcode= 2010PNAS..10713707F |doi= 10.1073/pnas.1002162107 |pmc=2922245|doi-access=free}}</ref> Recent computational redesign by Costas Maranas and coworkers was also capable of experimentally switching the [[cofactor (biochemistry)|cofactor]] specificity of ''Candida boidinii'' xylose reductase from [[Nicotinamide adenine dinucleotide phosphate|NADPH]] to [[Nicotinamide adenine dinucleotide|NADH]].<ref name="khoury">{{cite journal |title=Computational design of Candida boidinii xylose reductase for altered cofactor specificity |journal=Protein Science |volume=18 |issue=10 |pages=2125–38 |date=October 2009 |doi=10.1002/pro.227 |pmc=2786976 |pmid=19693930 |last1=Khoury |first1=GA |last2=Fazelinia |first2=H |last3=Chin |first3=JW |last4=Pantazes |first4=RJ |last5=Cirino |first5=PC |last6=Maranas |first6=CD}}</ref>