Editing Structural bioinformatics (section)

== Structure prediction ==

[[Image:1axc PCNA ProCheck Rama.jpg|thumb|200px|right| A Ramachandran plot generated from human [[PCNA]] ([[Protein Data Bank|PDB]] ID 1AXC). The red, brown, and yellow regions represent the favored, allowed, and "generously allowed" regions as defined by ProCheck. This plot can be used to verify incorrectly modeled amino acids.]]The atomic structures of molecules can be obtained by several methods, such as [[X-ray crystallography|X-ray crystallography (XRC)]], [[Nuclear magnetic resonance spectroscopy|NMR spectroscopy]], and [[Electron microscope|3D electron microscopy]]; however, these processes can present high costs and sometimes some structures can be hardly established, such as [[membrane protein]]s. Hence, it is necessary to use computational approaches for determining 3D structures of macromolecules. The structure prediction methods are classified into [[Homology modeling|comparative modeling]] and [[De novo protein structure prediction|de novo modeling]].

=== Comparative modeling ===
[[Homology modeling|Comparative modeling]], also known as homology modeling, corresponds to the methodology to construct three-dimensional structures from an [[amino acid]] sequence of a target protein and a template with known structure. The literature has described that evolutionarily related proteins tend to present a conserved three-dimensional structure.<ref>{{Cite journal|last1=Kaczanowski|first1=Szymon|last2=Zielenkiewicz|first2=Piotr | name-list-style = vanc |date=March 2010|title=Why similar protein sequences encode similar three-dimensional structures?|journal=Theoretical Chemistry Accounts|language=en|volume=125|issue=3–6|pages=643–650|doi=10.1007/s00214-009-0656-3|s2cid=95593331|issn=1432-881X|url=http://eprints.ibb.waw.pl/21/1/publikcja1.pdf}}</ref> In addition, sequences of distantly related proteins with identity lower than 20% can present different folds.<ref>{{cite journal | vauthors = Chothia C, Lesk AM | title = The relation between the divergence of sequence and structure in proteins | journal = The EMBO Journal | volume = 5 | issue = 4 | pages = 823–6 | date = April 1986 | pmid = 3709526 | pmc = 1166865 | doi = 10.1002/j.1460-2075.1986.tb04288.x }}</ref>

=== ''De novo'' modeling ===
In structural bioinformatics, [[De novo protein structure prediction|''de novo'' modeling]], also known as ''ab initio'' modeling, refers to approaches for obtaining three-dimensional structures from sequences without the necessity of a homologous known 3D structure. Despite the new algorithms and methods proposed in the last years, de novo protein structure prediction is still considered one of the remain outstanding issues in modern science.<ref>{{cite journal | title = So much more to know | journal = Science | volume = 309 | issue = 5731 | pages = 78–102 | date = July 2005 | pmid = 15994524 | doi = 10.1126/science.309.5731.78b | doi-access = free }}</ref>

=== Structure validation ===
After structure modeling, an additional step of structure validation is necessary since many of both comparative and 'de novo' modeling algorithms and tools use [[heuristic]]s to try assembly the 3D structure, which can generate many errors. Some validation strategies consist of calculating energy scores and comparing them with experimentally determined structures. For example, the [[Discrete optimized protein energy|DOPE score]] is an energy score used by the [[MODELLER|MODELLER tool]] for determining the best model.<ref>{{cite journal | vauthors = Webb B, Sali A | title = Comparative Protein Structure Modeling Using MODELLER | journal = Current Protocols in Bioinformatics | volume = 47 | issue = 1 | pages = 5.6.1–32 | date = September 2014 | pmid = 25199792 | doi = 10.1002/0471250953.bi0506s47 | pmc = 4186674 }}</ref>

Another validation strategy is calculating φ and ψ backbone dihedral angles of all residues and construct a [[Ramachandran plot]]. The side-chain of [[amino acid]]s and the nature of interactions in the backbone restrict these two angles, and thus, the visualization of allowed conformations could be performed based on the [[Ramachandran plot]]. A high quantity of amino acids allocated in no permissive positions of the chart is an indication of a low-quality modeling.

=== Prediction tools ===
A list with commonly used software tools for [[protein structure prediction]], including [[Homology modeling|comparative modeling]], [[protein threading]], ''[[De novo protein structure prediction|de novo]]'' [[De novo protein structure prediction|protein structure prediction]], and [[Protein structure prediction#Secondary structure|secondary structure prediction]] is available in the '''[[list of protein structure prediction software]].'''