Editing Protein structure prediction (section)

===''Ab initio'' protein modelling===
{{Main|De novo protein structure prediction}}

====Energy- and fragment-based methods====
''Ab initio''- or ''de novo''- protein modelling methods seek to build three-dimensional protein models "from scratch", i.e., based on physical principles rather than (directly) on previously solved structures. There are many possible procedures that either attempt to mimic [[protein folding]] or apply some [[stochastic]] method to search possible solutions (i.e., [[global optimization]] of a suitable energy function). These procedures tend to require vast computational resources, and have thus only been carried out for tiny proteins. To predict protein structure ''de novo'' for larger proteins will require better algorithms and larger computational resources like those afforded by either powerful supercomputers (such as [[Blue Gene]] or [[MDGRAPE-3]]) or distributed computing (such as [[Folding@home]], the [[Human Proteome Folding Project]] and [[Rosetta@Home]]). Although these computational barriers are vast, the potential benefits of structural genomics (by predicted or experimental methods) make ''ab initio'' structure prediction an active research field.<ref name="zhang2008">{{cite journal |vauthors=Zhang Y |title=Progress and challenges in protein structure prediction |journal=Current Opinion in Structural Biology |volume=18 |issue=3 |pages=342–8 |date=June 2008 |pmid=18436442 |pmc=2680823 |doi=10.1016/j.sbi.2008.02.004}}</ref>

As of 2009, a 50-residue protein could be simulated atom-by-atom on a supercomputer for 1 millisecond.<ref name="ShawBowers2009">{{cite conference| vauthors=Shaw DE, Dror RO, Salmon JK, Grossman JP, Mackenzie KM, Bank JA, Young C, Deneroff MM, Batson B, Bowers KJ, Chow E |conference=Proceedings of the Conference on High Performance Computing Networking, Storage and Analysis – SC '09 |year=2009|pages=1|doi=10.1145/1654059.1654126|title=Millisecond-scale molecular dynamics simulations on Anton|isbn=9781605587448|doi-access=}}</ref> As of 2012, comparable stable-state sampling could be done on a standard desktop with a new graphics card and more sophisticated algorithms.<ref name="PierceSalomon-Ferrer2012">{{cite journal |vauthors=Pierce LC, Salomon-Ferrer R, de Oliveira CA, McCammon JA, Walker RC |title=Routine Access to Millisecond Time Scale Events with Accelerated Molecular Dynamics |journal=Journal of Chemical Theory and Computation |volume=8 |issue=9 |pages=2997–3002 |date=September 2012 |pmid=22984356 |pmc=3438784 |doi=10.1021/ct300284c}}</ref> A much larger simulation timescales can be achieved using [[coarse-grained modeling]].<ref>{{cite journal |vauthors=Kmiecik S, Gront D, Kolinski M, Wieteska L, Dawid AE, Kolinski A |title=Coarse-Grained Protein Models and Their Applications |journal=Chemical Reviews |volume=116 |issue=14 |pages=7898–936 |date=July 2016 |pmid=27333362 |doi=10.1021/acs.chemrev.6b00163 |doi-access=free}}</ref><ref name="denovo2018">{{cite journal |vauthors=Cheung NJ, Yu W |title=De novo protein structure prediction using ultra-fast molecular dynamics simulation |journal=PLOS ONE |volume=13| issue=11 |pages=e0205819 |date=November 2018 |pmid=30458007 |pmc=6245515 |doi=10.1371/journal.pone.0205819 |bibcode=2018PLoSO..1305819C |doi-access=free}}</ref>

====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>