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The '''contact order''' of a [[protein]] is a measure of the locality of the inter-[[amino acid]] contacts in the protein's [[native state]] [[tertiary structure]]. It is calculated as the average sequence distance between residues that form [[native contact]]s in the folded protein divided by the total length of the protein. Higher contact orders indicate longer [[protein folding|folding times]],<ref name=plaxco>Plaxco, K. W., Simons, K. T., and Baker, D. (1998). Contact order, transition state placement, and the refolding rates of single domain proteins. ''J. Mol. Biol.'' 277, 985-994.</ref><ref name="Bonneau">Bonneau R, Ruczinski I, Tsai J, Baker D. (2002). Contact order and ab initio protein structure prediction. ''Protein Sci'' 11(8):1937-44.</ref> and low contact order has been suggested as a predictor of potential [[downhill folding]], or protein folding that occurs without a [[Thermodynamic free energy|free energy]] barrier.<ref name="Zuo">Zuo G, Wang J, Wang W. (2006). Folding with downhill behavior and low cooperativity of proteins. ''Proteins'' 63(1):165-73.</ref> This effect is thought to be due to the lower loss of [[conformational entropy]] associated with the formation of local as opposed to nonlocal contacts.<ref name="Bonneau" /> | |||
Contact order (CO) is formally defined as: | |||
:<math>CO={1 \over {L\cdot N}}\sum^{N}\Delta S_{i,j}</math> | |||
where ''N'' is the total number of contacts, Δ''Si,j'' is the sequence separation, in residues, between contacting residues ''i'' and ''j'', and ''L'' is the total number of residues in the protein.<ref name=plaxco /> The value of contact order typically ranges from 5% to 25% for single-domain proteins, with lower contact order belonging to mainly helical proteins, and higher contact order belonging to proteins with a high beta-sheet content. | |||
[[Protein structure prediction]] methods are more accurate in predicting the structures of proteins with low contact orders. This may be partly because low contact order proteins tend to be small, but is likely to be explained by the smaller number of possible long-range residue-residue interactions to be considered during [[global optimization]] procedures that minimize an [[objective function|energy function]].<ref name="Mount">Mount DM. (2004). ''Bioinformatics: Sequence and Genome Analysis'' 2nd ed. Cold Spring Harbor Laboratory Press: Cold Spring Harbor, NY.</ref> Even successful structure prediction methods such as the [[Rosetta@Home|Rosetta]] method overproduce low-contact-order structure predictions compared to the distributions observed in experimentally determined protein structures.<ref name="Bonneau" /> | |||
The percentage of the natively folded contact order can also be used as a measure of the "nativeness" of folding [[transition state]]s. [[Phi value analysis]] in concert with [[molecular dynamics]] has produced transition-state models whose contact order is close to that of the folded state in proteins that are small and fast-folding.<ref name="Pandit">Pandit AD, Jha A, Freed KF, Sosnick TR. (2006). Small proteins fold through transition states with native-like topologies. ''J Mol Biol'' 361(4):755-70.</ref> Further, contact orders in transition states as well as those in native states are highly correlated with overall folding time.<ref name="Paci">Paci E, Lindorff-Larsen K, Dobson CM, Karplus M, Vendruscolo M. (2005). Transition state contact orders correlate with protein folding rates. ''J Mol Biol'' 352(3):495-500.</ref> | |||
In addition to their role in structure prediction, contact orders can themselves be predicted based on a [[sequence alignment]], which can be useful in classifying the fold of a novel sequence with some degree of [[homology (biology)|homology]] to known sequences.<ref name="Shi">Yi Shi, Jianjun Zhou, David Arndt, David S. Wishart and Guohui Lin (2008). Protein contact order prediction from primary sequences. ''BMC Bioinformatics.'' 9:255.</ref> | |||
==References== | |||
<references /> | |||
[[Category:Bioinformatics]] | |||
[[Category:Protein structure]] | |||
Revision as of 23:18, 3 April 2013
The contact order of a protein is a measure of the locality of the inter-amino acid contacts in the protein's native state tertiary structure. It is calculated as the average sequence distance between residues that form native contacts in the folded protein divided by the total length of the protein. Higher contact orders indicate longer folding times,[1][2] and low contact order has been suggested as a predictor of potential downhill folding, or protein folding that occurs without a free energy barrier.[3] This effect is thought to be due to the lower loss of conformational entropy associated with the formation of local as opposed to nonlocal contacts.[2]
Contact order (CO) is formally defined as:
where N is the total number of contacts, ΔSi,j is the sequence separation, in residues, between contacting residues i and j, and L is the total number of residues in the protein.[1] The value of contact order typically ranges from 5% to 25% for single-domain proteins, with lower contact order belonging to mainly helical proteins, and higher contact order belonging to proteins with a high beta-sheet content.
Protein structure prediction methods are more accurate in predicting the structures of proteins with low contact orders. This may be partly because low contact order proteins tend to be small, but is likely to be explained by the smaller number of possible long-range residue-residue interactions to be considered during global optimization procedures that minimize an energy function.[4] Even successful structure prediction methods such as the Rosetta method overproduce low-contact-order structure predictions compared to the distributions observed in experimentally determined protein structures.[2]
The percentage of the natively folded contact order can also be used as a measure of the "nativeness" of folding transition states. Phi value analysis in concert with molecular dynamics has produced transition-state models whose contact order is close to that of the folded state in proteins that are small and fast-folding.[5] Further, contact orders in transition states as well as those in native states are highly correlated with overall folding time.[6]
In addition to their role in structure prediction, contact orders can themselves be predicted based on a sequence alignment, which can be useful in classifying the fold of a novel sequence with some degree of homology to known sequences.[7]
References
- ↑ 1.0 1.1 Plaxco, K. W., Simons, K. T., and Baker, D. (1998). Contact order, transition state placement, and the refolding rates of single domain proteins. J. Mol. Biol. 277, 985-994.
- ↑ 2.0 2.1 2.2 Bonneau R, Ruczinski I, Tsai J, Baker D. (2002). Contact order and ab initio protein structure prediction. Protein Sci 11(8):1937-44.
- ↑ Zuo G, Wang J, Wang W. (2006). Folding with downhill behavior and low cooperativity of proteins. Proteins 63(1):165-73.
- ↑ Mount DM. (2004). Bioinformatics: Sequence and Genome Analysis 2nd ed. Cold Spring Harbor Laboratory Press: Cold Spring Harbor, NY.
- ↑ Pandit AD, Jha A, Freed KF, Sosnick TR. (2006). Small proteins fold through transition states with native-like topologies. J Mol Biol 361(4):755-70.
- ↑ Paci E, Lindorff-Larsen K, Dobson CM, Karplus M, Vendruscolo M. (2005). Transition state contact orders correlate with protein folding rates. J Mol Biol 352(3):495-500.
- ↑ Yi Shi, Jianjun Zhou, David Arndt, David S. Wishart and Guohui Lin (2008). Protein contact order prediction from primary sequences. BMC Bioinformatics. 9:255.