Editing Protein structure prediction (section)

====Evolutionary covariation to predict 3D contacts====
As sequencing became more commonplace in the 1990s several groups used protein sequence alignments to predict correlated [[mutation]]s and it was hoped that these coevolved residues could be used to predict tertiary structure (using the analogy to distance constraints from experimental procedures such as [[NMR]]). The assumption is when single residue mutations are slightly deleterious, compensatory mutations may occur to restabilize residue-residue interactions.
This early work used what are known as ''local'' methods to calculate correlated mutations from protein sequences, but suffered from indirect false correlations which result from treating each pair of residues as independent of all other pairs.<ref>{{cite journal |vauthors=Göbel U, Sander C, Schneider R, Valencia A |title=Correlated mutations and residue contacts in proteins |journal=Proteins |volume=18 |issue=4 |pages=309–17 |date=April 1994 |pmid=8208723 |doi=10.1002/prot.340180402 |s2cid=14978727}}</ref><ref>{{cite journal |vauthors=Taylor WR, Hatrick K |title=Compensating changes in protein multiple sequence alignments |journal=Protein Engineering |volume=7 |issue=3 |pages=341–8 |date=March 1994 |pmid=8177883 |doi=10.1093/protein/7.3.341}}</ref><ref>{{cite journal |vauthors=Neher E |title=How frequent are correlated changes in families of protein sequences? |journal=Proceedings of the National Academy of Sciences of the United States of America |volume=91 |issue=1 |pages=98–102 |date=January 1994 |pmid=8278414 |pmc=42893 |doi=10.1073/pnas.91.1.98 |bibcode=1994PNAS...91...98N |doi-access=free}}</ref>

In 2011, a different, and this time ''global'' statistical approach, demonstrated that predicted coevolved residues were sufficient to predict the 3D fold of a protein, providing there are enough sequences available (>1,000 homologous sequences are needed).<ref name="marks">{{cite journal |vauthors=Marks DS, Colwell LJ, Sheridan R, Hopf TA, Pagnani A, Zecchina R, Sander C |title=Protein 3D structure computed from evolutionary sequence variation |journal=PLOS ONE |volume=6 |issue=12 |pages=e28766 |year=2011 |pmid=22163331 |pmc=3233603 |doi=10.1371/journal.pone.0028766 |bibcode=2011PLoSO...628766M |doi-access=free}}</ref> The method, [http://evfold.org EVfold], uses no homology modeling, threading or 3D structure fragments and can be run on a standard personal computer even for proteins with hundreds of residues. The accuracy of the contacts predicted using this and related approaches has now been demonstrated on many known structures and contact maps,<ref>{{cite journal |vauthors=Burger L, van Nimwegen E |title=Disentangling direct from indirect co-evolution of residues in protein alignments |journal=PLOS Computational Biology |volume=6 |issue=1 |pages=e1000633 |date=January 2010 |pmid=20052271 |pmc=2793430 |doi=10.1371/journal.pcbi.1000633 |bibcode=2010PLSCB...6E0633B |doi-access=free}}</ref><ref>{{cite journal |vauthors=Morcos F, Pagnani A, Lunt B, Bertolino A, Marks DS, Sander C, Zecchina R, Onuchic JN, Hwa T, Weigt M |title=Direct-coupling analysis of residue coevolution captures native contacts across many protein families |journal=Proceedings of the National Academy of Sciences of the United States of America |volume=108 |issue=49 |pages=E1293-301 |date=December 2011 |pmid=22106262 |pmc=3241805 |doi=10.1073/pnas.1111471108 |arxiv=1110.5223 |bibcode=2011PNAS..108E1293M |doi-access=free}}</ref><ref>{{cite journal |vauthors=Nugent T, Jones DT |title=Accurate de novo structure prediction of large transmembrane protein domains using fragment-assembly and correlated mutation analysis |journal=Proceedings of the National Academy of Sciences of the United States of America |volume=109 |issue=24 |pages=E1540-7 |date=June 2012 |pmid=22645369 |pmc=3386101 |doi=10.1073/pnas.1120036109 |bibcode=2012PNAS..109E1540N |doi-access=free}}</ref> including the prediction of experimentally unsolved transmembrane proteins.<ref>{{cite journal |vauthors=Hopf TA, Colwell LJ, Sheridan R, Rost B, Sander C, Marks DS |title=Three-dimensional structures of membrane proteins from genomic sequencing |journal=Cell |volume=149 |issue=7 |pages=1607–21 |date=June 2012 |pmid=22579045 |pmc=3641781 |doi=10.1016/j.cell.2012.04.012}}</ref>