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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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Coevolution between catalytic sites.All catalytic sites annotated by the CSA [30] and tested for coevolution (i.e.≤20% gaps) are depicted in red. The protein backbones are depicted as a white ribbon. Coevolving catalytic residues are connected by orange lines. (A) Active site of murine adenosine deaminase (PF00962, PDB 1a4l) [38]. The inhibitor, pentostatin, and a coordinating Zn2+ ion are depicted in blue. The coordinating interactions with Zn2+ is depicted as purple lines [38]. (B) The nucleotide binding site of Methanosarcina thermophila acetate kinase (PF00871, PDB 1g99) [39]. The bound ADP molecule and a sulfate ion are depicted in blue. (C) Active site of Pseudomonas fluorescens carboxylesterase (PF02230, PDB 1aur) [40]. The inhibitor, phenylmethylsulfonyl fluoride, is covalently bound to Ser114 and its phenylmethylsulfonyl moiety is depicted in blue.
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pone-0004762-g008: Coevolution between catalytic sites.All catalytic sites annotated by the CSA [30] and tested for coevolution (i.e.≤20% gaps) are depicted in red. The protein backbones are depicted as a white ribbon. Coevolving catalytic residues are connected by orange lines. (A) Active site of murine adenosine deaminase (PF00962, PDB 1a4l) [38]. The inhibitor, pentostatin, and a coordinating Zn2+ ion are depicted in blue. The coordinating interactions with Zn2+ is depicted as purple lines [38]. (B) The nucleotide binding site of Methanosarcina thermophila acetate kinase (PF00871, PDB 1g99) [39]. The bound ADP molecule and a sulfate ion are depicted in blue. (C) Active site of Pseudomonas fluorescens carboxylesterase (PF02230, PDB 1aur) [40]. The inhibitor, phenylmethylsulfonyl fluoride, is covalently bound to Ser114 and its phenylmethylsulfonyl moiety is depicted in blue.

Mentions: While catalytic sites did not demonstrate any increased tendency towards having coevolutionary partners in general, we wondered whether catalytic sites tended to coevolve specifically with each other. Of the 257 PDB structures with CSA entries, 175 contained at least two catalytic sites and were used for our subsequent analysis. We found that 61 of these PDB structures contained at least one pair of catalytic sites identified as coevolving with each other. In total, there were 90 such coevolving pairs of catalytic sites, representing 11% of all possible catalytic site pairs (793). To determine whether this propensity for catalytic sites to coevolve with one another was significantly higher than random expectations, for each representative structure, we selected random sites equal in number to the number of catalytic sites and asked how many of these random sites coevolved with one another. Over 2000 randomizations, the average total number of coevolving pairs of random sites was only 6.5±2.7 (0.8%), significantly fewer than the number of coevolving pairs of catalytic sites identified (in all 2000 randomizations, the randomly selected sites never shared 90 or more coevolutionary pairing; given a normal fit of the random results log transformed to satisfy normalcy, we calculated the probability of getting 90 or more coevolving pairs to be less than 1×10−16). Repeating the analysis with random sites chosen under the requirement that all selected sites for a protein be contacting each other in the representative structure, only 56.7±7.2 (7.2%) were identified as coevolving, showing that the tendency for catalytic sites to coevolve could not be completely explained by any tendency to be located near each other at active sites (p<1×10−16). Three example proteins containing coevolving catalytic sites have been depicted in Figure 8.


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

Little DY, Chen L - PLoS ONE (2009)

Coevolution between catalytic sites.All catalytic sites annotated by the CSA [30] and tested for coevolution (i.e.≤20% gaps) are depicted in red. The protein backbones are depicted as a white ribbon. Coevolving catalytic residues are connected by orange lines. (A) Active site of murine adenosine deaminase (PF00962, PDB 1a4l) [38]. The inhibitor, pentostatin, and a coordinating Zn2+ ion are depicted in blue. The coordinating interactions with Zn2+ is depicted as purple lines [38]. (B) The nucleotide binding site of Methanosarcina thermophila acetate kinase (PF00871, PDB 1g99) [39]. The bound ADP molecule and a sulfate ion are depicted in blue. (C) Active site of Pseudomonas fluorescens carboxylesterase (PF02230, PDB 1aur) [40]. The inhibitor, phenylmethylsulfonyl fluoride, is covalently bound to Ser114 and its phenylmethylsulfonyl moiety is depicted in blue.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2651771&req=5

pone-0004762-g008: Coevolution between catalytic sites.All catalytic sites annotated by the CSA [30] and tested for coevolution (i.e.≤20% gaps) are depicted in red. The protein backbones are depicted as a white ribbon. Coevolving catalytic residues are connected by orange lines. (A) Active site of murine adenosine deaminase (PF00962, PDB 1a4l) [38]. The inhibitor, pentostatin, and a coordinating Zn2+ ion are depicted in blue. The coordinating interactions with Zn2+ is depicted as purple lines [38]. (B) The nucleotide binding site of Methanosarcina thermophila acetate kinase (PF00871, PDB 1g99) [39]. The bound ADP molecule and a sulfate ion are depicted in blue. (C) Active site of Pseudomonas fluorescens carboxylesterase (PF02230, PDB 1aur) [40]. The inhibitor, phenylmethylsulfonyl fluoride, is covalently bound to Ser114 and its phenylmethylsulfonyl moiety is depicted in blue.
Mentions: While catalytic sites did not demonstrate any increased tendency towards having coevolutionary partners in general, we wondered whether catalytic sites tended to coevolve specifically with each other. Of the 257 PDB structures with CSA entries, 175 contained at least two catalytic sites and were used for our subsequent analysis. We found that 61 of these PDB structures contained at least one pair of catalytic sites identified as coevolving with each other. In total, there were 90 such coevolving pairs of catalytic sites, representing 11% of all possible catalytic site pairs (793). To determine whether this propensity for catalytic sites to coevolve with one another was significantly higher than random expectations, for each representative structure, we selected random sites equal in number to the number of catalytic sites and asked how many of these random sites coevolved with one another. Over 2000 randomizations, the average total number of coevolving pairs of random sites was only 6.5±2.7 (0.8%), significantly fewer than the number of coevolving pairs of catalytic sites identified (in all 2000 randomizations, the randomly selected sites never shared 90 or more coevolutionary pairing; given a normal fit of the random results log transformed to satisfy normalcy, we calculated the probability of getting 90 or more coevolving pairs to be less than 1×10−16). Repeating the analysis with random sites chosen under the requirement that all selected sites for a protein be contacting each other in the representative structure, only 56.7±7.2 (7.2%) were identified as coevolving, showing that the tendency for catalytic sites to coevolve could not be completely explained by any tendency to be located near each other at active sites (p<1×10−16). Three example proteins containing coevolving catalytic sites have been depicted in Figure 8.

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
Related in: MedlinePlus