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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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Joint distribution of intra-molecular and inter-molecular distances between coevolving residues.532 protein and domain alignments whose representative PDB structures contained multiple copies of the corresponding peptide were used for the analysis. The color of each cell depicts the fraction of all residues pairs lying within the specified intervals of intra-molecular and inter-molecular distances that are coevolving. Coevolving pairs are particularly prevalent amongst residues pairs that lie in close physical proximity to each other either intra-molecularly or inter-molecularly.
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pone-0004762-g007: Joint distribution of intra-molecular and inter-molecular distances between coevolving residues.532 protein and domain alignments whose representative PDB structures contained multiple copies of the corresponding peptide were used for the analysis. The color of each cell depicts the fraction of all residues pairs lying within the specified intervals of intra-molecular and inter-molecular distances that are coevolving. Coevolving pairs are particularly prevalent amongst residues pairs that lie in close physical proximity to each other either intra-molecularly or inter-molecularly.

Mentions: To further test this hypothesis, we identified 532 alignments whose representative crystal structure contained multiple copies of the aligned protein. Since the formation of protein crystals inherently imposes a multimerization of the peptides, we restricted our analysis to only those chains in the structure identified as being part of a biologically relevant assembly (“REMARK 350” in PDB files) [23]. Plotting the joint histogram of intra-molecular and inter-molecular distances for the coevolving sites normalized to the joint histogram for all tested sites, we found that the coevolving site pairs were particularly represented amongst those that were physically close either within a protein or between interacting copies of the protein (Figure 7). Of all 9207 residues pairs that were within 6 Å of each other in inter-molecular distance, over 10% (1167 pairs) of them were identified as coevolving. In comparison, only 0.7% of all site-pairs (distant or close) were selected as coevolving. The percentage of intra-molecularly contacting residue pairs (less than 6 Å apart) rose from 6.23% for all tested pairs to 58.20% for coevolving pairs, while the percentage of inter-molecularly contacting residues rose from 0.34% to 2.59%. These results clearly demonstrate the importance of inter-molecular interactions in the coevolution of residues.


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

Little DY, Chen L - PLoS ONE (2009)

Joint distribution of intra-molecular and inter-molecular distances between coevolving residues.532 protein and domain alignments whose representative PDB structures contained multiple copies of the corresponding peptide were used for the analysis. The color of each cell depicts the fraction of all residues pairs lying within the specified intervals of intra-molecular and inter-molecular distances that are coevolving. Coevolving pairs are particularly prevalent amongst residues pairs that lie in close physical proximity to each other either intra-molecularly or inter-molecularly.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0004762-g007: Joint distribution of intra-molecular and inter-molecular distances between coevolving residues.532 protein and domain alignments whose representative PDB structures contained multiple copies of the corresponding peptide were used for the analysis. The color of each cell depicts the fraction of all residues pairs lying within the specified intervals of intra-molecular and inter-molecular distances that are coevolving. Coevolving pairs are particularly prevalent amongst residues pairs that lie in close physical proximity to each other either intra-molecularly or inter-molecularly.
Mentions: To further test this hypothesis, we identified 532 alignments whose representative crystal structure contained multiple copies of the aligned protein. Since the formation of protein crystals inherently imposes a multimerization of the peptides, we restricted our analysis to only those chains in the structure identified as being part of a biologically relevant assembly (“REMARK 350” in PDB files) [23]. Plotting the joint histogram of intra-molecular and inter-molecular distances for the coevolving sites normalized to the joint histogram for all tested sites, we found that the coevolving site pairs were particularly represented amongst those that were physically close either within a protein or between interacting copies of the protein (Figure 7). Of all 9207 residues pairs that were within 6 Å of each other in inter-molecular distance, over 10% (1167 pairs) of them were identified as coevolving. In comparison, only 0.7% of all site-pairs (distant or close) were selected as coevolving. The percentage of intra-molecularly contacting residue pairs (less than 6 Å apart) rose from 6.23% for all tested pairs to 58.20% for coevolving pairs, while the percentage of inter-molecularly contacting residues rose from 0.34% to 2.59%. These results clearly demonstrate the importance of inter-molecular interactions in the coevolution of residues.

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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