Editing Protein design (section)

===Structural flexibility===
[[File:ileRotamers.gif|thumb|left|200px|Common protein design programs use rotamer libraries to simplify the conformational space of protein side chains. This animation loops through all the rotamers of the isoleucine amino acid based on the Penultimate Rotamer Library (total of 7 rotamers).<ref name="lovell2000" />]]

In protein design, the target structure (or structures) of the protein are known. However, a rational protein design approach must model some ''flexibility'' on the target structure in order to increase the number of sequences that can be designed for that structure and to minimize the chance of a sequence folding to a different structure. For example, in a protein redesign of one small amino acid (such as alanine) in the tightly packed core of a protein, very few mutants would be predicted by a rational design approach to fold to the target structure, if the surrounding side-chains are not allowed to be repacked.

Thus, an essential parameter of any design process is the amount of flexibility allowed for both the side-chains and the backbone. In the simplest models, the protein backbone is kept rigid while some of the protein side-chains are allowed to change conformations. However, side-chains can have many degrees of freedom in their bond lengths, bond angles, and [[Dihedral angle#Dihedral angles of biological molecules|<var>&chi;</var> dihedral angles]]. To simplify this space, protein design methods use rotamer libraries that assume ideal values for bond lengths and bond angles, while restricting <var>&chi;</var> dihedral angles to a few frequently observed low-energy conformations termed [[Conformational isomerism|rotamers]].

Rotamer libraries are derived from the statistical analysis of many protein structures. Backbone-independent rotamer libraries describe all rotamers.<ref name="lovell2000">{{cite journal|last=Lovell|first=SC|author2=Word, JM |author3=Richardson, JS |author4= Richardson, DC |title=The penultimate rotamer library.|journal=Proteins|date=August 15, 2000|volume=40|issue=3|pages=389–408|pmid=10861930|doi=10.1002/1097-0134(20000815)40:3<389::AID-PROT50>3.0.CO;2-2|citeseerx=10.1.1.555.4071|s2cid=3055173 }}</ref> [[Backbone-dependent rotamer library|Backbone-dependent rotamer libraries]], in contrast, describe the rotamers as how likely they are to appear depending on the protein backbone arrangement around the side chain.<ref>{{cite journal|last=Shapovalov|first=MV|author2=Dunbrack RL, Jr|title=A smoothed backbone-dependent rotamer library for proteins derived from adaptive kernel density estimates and regressions.|journal=Structure|date=June 8, 2011|volume=19|issue=6|pages=844–58|pmid=21645855|doi=10.1016/j.str.2011.03.019|pmc=3118414}}</ref> Most protein design programs use one conformation (e.g., the modal value for rotamer dihedrals in space) or several points in the region described by the rotamer; the OSPREY protein design program, in contrast, models the entire continuous region.<ref name="samish11"/>

Although rational protein design must preserve the general backbone fold a protein, allowing some backbone flexibility can significantly increase the number of sequences that fold to the structure while maintaining the general fold of the protein.<ref name="kortemme09">{{cite journal|last=Mandell|first=DJ|author2=Kortemme, T |author-link2=Tanja Kortemme |title=Backbone flexibility in computational protein design.|journal=Current Opinion in Biotechnology|date=August 2009|volume=20|issue=4|pages=420–8|pmid=19709874|doi=10.1016/j.copbio.2009.07.006|url=https://escholarship.org/content/qt89b8n09b/qt89b8n09b.pdf?t=pqrxq4}}</ref> Backbone flexibility is especially important in protein redesign because sequence mutations often result in small changes to the backbone structure. Moreover, backbone flexibility can be essential for more advanced applications of protein design, such as binding prediction and enzyme design. Some models of protein design backbone flexibility include small and continuous global backbone movements, discrete backbone samples around the target fold, backrub motions, and protein loop flexibility.<ref name="kortemme09" /><ref name="donald10" />