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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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Inter-molecular interactions between coevolving residues of the chorismate synthase tetramer.(A–C) Coevolving residues are highlighted by the same hue. Light residues are from chain A. Dark residues are from chain D (panels A and B) or chain C (panel C). (B) The back side of the structure depicted in panel A. (D) A pair of coevolving residues forming a planar ring at the center of the tetramer. Each molecule of chorismate synthase is depicted in a different color.
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pone-0004762-g006: Inter-molecular interactions between coevolving residues of the chorismate synthase tetramer.(A–C) Coevolving residues are highlighted by the same hue. Light residues are from chain A. Dark residues are from chain D (panels A and B) or chain C (panel C). (B) The back side of the structure depicted in panel A. (D) A pair of coevolving residues forming a planar ring at the center of the tetramer. Each molecule of chorismate synthase is depicted in a different color.

Mentions: A surprising result from an examination of the coevolving residues of chorismate synthase offered a partial explanation as to why coevolving residue pairs that are distant in their representative structures are still correlated to the MJ contact energies. Chorismate synthase is a homotetramerizing protein important in the synthesis of aromatic compounds in bacteria, and its crystal structure has been solved (PDB ID: 1UM0) [29]. Examining the distribution of distances between residues within a single chain of chorismate synthase (chain A in the representative crystal structure), we again found that the coevolving residue pairs were significantly closer together than all tested residue pairs (Figure S5; p<1×10∧−48, K-S test; median distances: 5.78 Å (coevolving), 23.63 Å (all)). Interestingly, when we began mapping the strongest coevolving sites onto the crystal structure of the chorismate synthase tetramer, we found that many of them were directly apposed to each other across the dimer interfaces (Figure 6A–C). Amongst the top 50 ZRes scoring residue pairs, 34 residue pairs (68%) were found to be contacting each other (≤6 Å apart) within a single molecule of chorismate synthase (chain A). Of the 16 pairs that were not in intra-molecular contact, 9 were found to be in contact between molecules of the tetramer (Figure 6A–C) and an additional pair was found to form a planar ring at the interface of the four chains (Lys-232 and Leu-349; Figure 6D). Many of these coevolving residues were predicted by UCSF Chimera to form inter-molecular hydrogen bonds (data not shown) [25]. Taken together with the previous results, this suggests that residues may coevolve to maintain structural interactions both within and between protein molecules.


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

Little DY, Chen L - PLoS ONE (2009)

Inter-molecular interactions between coevolving residues of the chorismate synthase tetramer.(A–C) Coevolving residues are highlighted by the same hue. Light residues are from chain A. Dark residues are from chain D (panels A and B) or chain C (panel C). (B) The back side of the structure depicted in panel A. (D) A pair of coevolving residues forming a planar ring at the center of the tetramer. Each molecule of chorismate synthase is depicted in a different color.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2651771&req=5

pone-0004762-g006: Inter-molecular interactions between coevolving residues of the chorismate synthase tetramer.(A–C) Coevolving residues are highlighted by the same hue. Light residues are from chain A. Dark residues are from chain D (panels A and B) or chain C (panel C). (B) The back side of the structure depicted in panel A. (D) A pair of coevolving residues forming a planar ring at the center of the tetramer. Each molecule of chorismate synthase is depicted in a different color.
Mentions: A surprising result from an examination of the coevolving residues of chorismate synthase offered a partial explanation as to why coevolving residue pairs that are distant in their representative structures are still correlated to the MJ contact energies. Chorismate synthase is a homotetramerizing protein important in the synthesis of aromatic compounds in bacteria, and its crystal structure has been solved (PDB ID: 1UM0) [29]. Examining the distribution of distances between residues within a single chain of chorismate synthase (chain A in the representative crystal structure), we again found that the coevolving residue pairs were significantly closer together than all tested residue pairs (Figure S5; p<1×10∧−48, K-S test; median distances: 5.78 Å (coevolving), 23.63 Å (all)). Interestingly, when we began mapping the strongest coevolving sites onto the crystal structure of the chorismate synthase tetramer, we found that many of them were directly apposed to each other across the dimer interfaces (Figure 6A–C). Amongst the top 50 ZRes scoring residue pairs, 34 residue pairs (68%) were found to be contacting each other (≤6 Å apart) within a single molecule of chorismate synthase (chain A). Of the 16 pairs that were not in intra-molecular contact, 9 were found to be in contact between molecules of the tetramer (Figure 6A–C) and an additional pair was found to form a planar ring at the interface of the four chains (Lys-232 and Leu-349; Figure 6D). Many of these coevolving residues were predicted by UCSF Chimera to form inter-molecular hydrogen bonds (data not shown) [25]. Taken together with the previous results, this suggests that residues may coevolve to maintain structural interactions both within and between protein molecules.

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