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Identification of coevolving residues and coevolution potentials emphasizing structure, bond formation and catalytic coordination in protein evolution.

Little DY, Chen L - PLoS ONE (2009)

Bottom Line: The selective pressures associated with a mutation at one site should therefore depend on the amino acid identity of interacting sites.Finally, we demonstrate that pairs of catalytic residues have a significantly increased likelihood to be identified as coevolving.These correlations to distinct protein features verify the accuracy of our algorithm and are consistent with a model of coevolution in which selective pressures towards preserving residue interactions act to shape the mutational landscape of a protein by restricting the set of admissible neutral mutations.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular and Cell Biology, University of California, Berkeley, California, United States of America.

ABSTRACT
The structure and function of a protein is dependent on coordinated interactions between its residues. The selective pressures associated with a mutation at one site should therefore depend on the amino acid identity of interacting sites. Mutual information has previously been applied to multiple sequence alignments as a means of detecting coevolutionary interactions. Here, we introduce a refinement of the mutual information method that: 1) removes a significant, non-coevolutionary bias and 2) accounts for heteroscedasticity. Using a large, non-overlapping database of protein alignments, we demonstrate that predicted coevolving residue-pairs tend to lie in close physical proximity. We introduce coevolution potentials as a novel measure of the propensity for the 20 amino acids to pair amongst predicted coevolutionary interactions. Ionic, hydrogen, and disulfide bond-forming pairs exhibited the highest potentials. Finally, we demonstrate that pairs of catalytic residues have a significantly increased likelihood to be identified as coevolving. These correlations to distinct protein features verify the accuracy of our algorithm and are consistent with a model of coevolution in which selective pressures towards preserving residue interactions act to shape the mutational landscape of a protein by restricting the set of admissible neutral mutations.

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Distribution of distances between coevolving residues of PDZ domains.The fraction of coevolving (black bars) or all (white bars) residue pairs that lie within the specified interval of physical distance from each other is depicted.
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pone-0004762-g003: Distribution of distances between coevolving residues of PDZ domains.The fraction of coevolving (black bars) or all (white bars) residue pairs that lie within the specified interval of physical distance from each other is depicted.

Mentions: The close physical proximity between each coevolving residue pair is quite striking. We plotted the distribution of distances between pairs of coevolving residues and compared it to the distribution of distances between all tested pairs of residues (Figure 3). We found that the interacting residues were significantly closer together (median distances: 2.88 Å (coevolving), 11.30 Å (all); p<1×10−16, 2-sample Kolmogorov-Smirnov (K-S test)). We interpret this as arising from a tendency for coevolving residues to be close to each other combined with the ability of our ZRes measure to accurately detect signals of coevolution. Interestingly, while many of the coevolving residues where found to lie in the same secondary structure (e.g. Val-83 and Lys-87 which align on one side of the only α-helix; Figure 2C), several examples were also found of residues interacting between secondary structures (e.g. Gln-68 and Ile-96 interacting between the 4th and 6th β-sheets; Figure 2D).


Identification of coevolving residues and coevolution potentials emphasizing structure, bond formation and catalytic coordination in protein evolution.

Little DY, Chen L - PLoS ONE (2009)

Distribution of distances between coevolving residues of PDZ domains.The fraction of coevolving (black bars) or all (white bars) residue pairs that lie within the specified interval of physical distance from each other is depicted.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2651771&req=5

pone-0004762-g003: Distribution of distances between coevolving residues of PDZ domains.The fraction of coevolving (black bars) or all (white bars) residue pairs that lie within the specified interval of physical distance from each other is depicted.
Mentions: The close physical proximity between each coevolving residue pair is quite striking. We plotted the distribution of distances between pairs of coevolving residues and compared it to the distribution of distances between all tested pairs of residues (Figure 3). We found that the interacting residues were significantly closer together (median distances: 2.88 Å (coevolving), 11.30 Å (all); p<1×10−16, 2-sample Kolmogorov-Smirnov (K-S test)). We interpret this as arising from a tendency for coevolving residues to be close to each other combined with the ability of our ZRes measure to accurately detect signals of coevolution. Interestingly, while many of the coevolving residues where found to lie in the same secondary structure (e.g. Val-83 and Lys-87 which align on one side of the only α-helix; Figure 2C), several examples were also found of residues interacting between secondary structures (e.g. Gln-68 and Ile-96 interacting between the 4th and 6th β-sheets; Figure 2D).

Bottom Line: The selective pressures associated with a mutation at one site should therefore depend on the amino acid identity of interacting sites.Finally, we demonstrate that pairs of catalytic residues have a significantly increased likelihood to be identified as coevolving.These correlations to distinct protein features verify the accuracy of our algorithm and are consistent with a model of coevolution in which selective pressures towards preserving residue interactions act to shape the mutational landscape of a protein by restricting the set of admissible neutral mutations.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular and Cell Biology, University of California, Berkeley, California, United States of America.

ABSTRACT
The structure and function of a protein is dependent on coordinated interactions between its residues. The selective pressures associated with a mutation at one site should therefore depend on the amino acid identity of interacting sites. Mutual information has previously been applied to multiple sequence alignments as a means of detecting coevolutionary interactions. Here, we introduce a refinement of the mutual information method that: 1) removes a significant, non-coevolutionary bias and 2) accounts for heteroscedasticity. Using a large, non-overlapping database of protein alignments, we demonstrate that predicted coevolving residue-pairs tend to lie in close physical proximity. We introduce coevolution potentials as a novel measure of the propensity for the 20 amino acids to pair amongst predicted coevolutionary interactions. Ionic, hydrogen, and disulfide bond-forming pairs exhibited the highest potentials. Finally, we demonstrate that pairs of catalytic residues have a significantly increased likelihood to be identified as coevolving. These correlations to distinct protein features verify the accuracy of our algorithm and are consistent with a model of coevolution in which selective pressures towards preserving residue interactions act to shape the mutational landscape of a protein by restricting the set of admissible neutral mutations.

Show MeSH