Phylogenetic inference

Interpreting phylogenetic trees

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Morcos et al. (2013) Coevolutionary signals across protein lineages help capture multiple protein conformations. Proc Natl Acad Sci U.S.A 110:20533-8. (pmid: 24297889)

[ PubMed ] [ DOI ] Abstract A long-standing problem in molecular biology is the determination of a complete functional conformational landscape of proteins. This includes not only proteins' native structures, but also all their respective functional states, including functionally important intermediates. Here, we reveal a signature of functionally important states in several protein families, using direct coupling analysis, which detects residue pair coevolution of protein sequence composition. This signature is exploited in a protein structure-based model to uncover conformational diversity, including hidden functional configurations. We uncovered, with high resolution (mean ~1.9 Å rmsd for nonapo structures), different functional structural states for medium to large proteins (200-450 aa) belonging to several distinct families. The combination of direct coupling analysis and the structure-based model also predicts several intermediates or hidden states that are of functional importance. This enhanced sampling is broadly applicable and has direct implications in protein structure determination and the design of ligands or drugs to trap intermediate states.

Cocco et al. (2013) From principal component to direct coupling analysis of coevolution in proteins: low-eigenvalue modes are needed for structure prediction. PLoS Comput Biol 9:e1003176. (pmid: 23990764)

[ PubMed ] [ DOI ] Abstract Various approaches have explored the covariation of residues in multiple-sequence alignments of homologous proteins to extract functional and structural information. Among those are principal component analysis (PCA), which identifies the most correlated groups of residues, and direct coupling analysis (DCA), a global inference method based on the maximum entropy principle, which aims at predicting residue-residue contacts. In this paper, inspired by the statistical physics of disordered systems, we introduce the Hopfield-Potts model to naturally interpolate between these two approaches. The Hopfield-Potts model allows us to identify relevant 'patterns' of residues from the knowledge of the eigenmodes and eigenvalues of the residue-residue correlation matrix. We show how the computation of such statistical patterns makes it possible to accurately predict residue-residue contacts with a much smaller number of parameters than DCA. This dimensional reduction allows us to avoid overfitting and to extract contact information from multiple-sequence alignments of reduced size. In addition, we show that low-eigenvalue correlation modes, discarded by PCA, are important to recover structural information: the corresponding patterns are highly localized, that is, they are concentrated in few sites, which we find to be in close contact in the three-dimensional protein fold.

Li et al. (2013) Coevolution of quantum and classical strategies on evolving random networks. PLoS ONE 8:e68423. (pmid: 23874622)

[ PubMed ] [ DOI ] Abstract We study the coevolution of quantum and classical strategies on weighted and directed random networks in the realm of the prisoner's dilemma game. During the evolution, agents can break and rewire their links with the aim of maximizing payoffs, and they can also adjust the weights to indicate preferences, either positive or negative, towards their neighbors. The network structure itself is thus also subject to evolution. Importantly, the directionality of links does not affect the accumulation of payoffs nor the strategy transfers, but serves only to designate the owner of each particular link and with it the right to adjust the link as needed. We show that quantum strategies outperform classical strategies, and that the critical temptation to defect at which cooperative behavior can be maintained rises, if the network structure is updated frequently. Punishing neighbors by reducing the weights of their links also plays an important role in maintaining cooperation under adverse conditions. We find that the self-organization of the initially random network structure, driven by the evolutionary competition between quantum and classical strategies, leads to the spontaneous emergence of small average path length and a large clustering coefficient.

Miyazawa (2013) Prediction of contact residue pairs based on co-substitution between sites in protein structures. PLoS ONE 8:e54252. (pmid: 23342110)

[ PubMed ] [ DOI ] Abstract Residue-residue interactions that fold a protein into a unique three-dimensional structure and make it play a specific function impose structural and functional constraints in varying degrees on each residue site. Selective constraints on residue sites are recorded in amino acid orders in homologous sequences and also in the evolutionary trace of amino acid substitutions. A challenge is to extract direct dependences between residue sites by removing phylogenetic correlations and indirect dependences through other residues within a protein or even through other molecules. Rapid growth of protein families with unknown folds requires an accurate de novo prediction method for protein structure. Recent attempts of disentangling direct from indirect dependences of amino acid types between residue positions in multiple sequence alignments have revealed that inferred residue-residue proximities can be sufficient information to predict a protein fold without the use of known three-dimensional structures. Here, we propose an alternative method of inferring coevolving site pairs from concurrent and compensatory substitutions between sites in each branch of a phylogenetic tree. Substitution probability and physico-chemical changes (volume, charge, hydrogen-bonding capability, and others) accompanied by substitutions at each site in each branch of a phylogenetic tree are estimated with the likelihood of each substitution, and their direct correlations between sites are used to detect concurrent and compensatory substitutions. In order to extract direct dependences between sites, partial correlation coefficients of the characteristic changes along branches between sites, in which linear multiple dependences on feature vectors at other sites are removed, are calculated and used to rank coevolving site pairs. Accuracy of contact prediction based on the present coevolution score is comparable to that achieved by a maximum entropy model of protein sequences for 15 protein families taken from the Pfam release 26.0. Besides, this excellent accuracy indicates that compensatory substitutions are significant in protein evolution.

Burkoff et al. (2013) Predicting protein β-sheet contacts using a maximum entropy-based correlated mutation measure. Bioinformatics 29:580-7. (pmid: 23314126)

[ PubMed ] [ DOI ] Abstract MOTIVATION: The problem of ab initio protein folding is one of the most difficult in modern computational biology. The prediction of residue contacts within a protein provides a more tractable immediate step. Recently introduced maximum entropy-based correlated mutation measures (CMMs), such as direct information, have been successful in predicting residue contacts. However, most correlated mutation studies focus on proteins that have large good-quality multiple sequence alignments (MSA) because the power of correlated mutation analysis falls as the size of the MSA decreases. However, even with small autogenerated MSAs, maximum entropy-based CMMs contain information. To make use of this information, in this article, we focus not on general residue contacts but contacts between residues in β-sheets. The strong constraints and prior knowledge associated with β-contacts are ideally suited for prediction using a method that incorporates an often noisy CMM. RESULTS: Using contrastive divergence, a statistical machine learning technique, we have calculated a maximum entropy-based CMM. We have integrated this measure with a new probabilistic model for β-contact prediction, which is used to predict both residue- and strand-level contacts. Using our model on a standard non-redundant dataset, we significantly outperform a 2D recurrent neural network architecture, achieving a 5% improvement in true positives at the 5% false-positive rate at the residue level. At the strand level, our approach is competitive with the state-of-the-art single methods achieving precision of 61.0% and recall of 55.4%, while not requiring residue solvent accessibility as an input. AVAILABILITY: http://www2.warwick.ac.uk/fac/sci/systemsbiology/research/software/

Ackerman et al. (2012) Accurate simulation and detection of coevolution signals in multiple sequence alignments. PLoS ONE 7:e47108. (pmid: 23091608)

[ PubMed ] [ DOI ] Abstract BACKGROUND: While the conserved positions of a multiple sequence alignment (MSA) are clearly of interest, non-conserved positions can also be important because, for example, destabilizing effects at one position can be compensated by stabilizing effects at another position. Different methods have been developed to recognize the evolutionary relationship between amino acid sites, and to disentangle functional/structural dependencies from historical/phylogenetic ones. METHODOLOGY/PRINCIPAL FINDINGS: We have used two complementary approaches to test the efficacy of these methods. In the first approach, we have used a new program, MSAvolve, for the in silico evolution of MSAs, which records a detailed history of all covarying positions, and builds a global coevolution matrix as the accumulated sum of individual matrices for the positions forced to co-vary, the recombinant coevolution, and the stochastic coevolution. We have simulated over 1600 MSAs for 8 protein families, which reflect sequences of different sizes and proteins with widely different functions. The calculated coevolution matrices were compared with the coevolution matrices obtained for the same evolved MSAs with different coevolution detection methods. In a second approach we have evaluated the capacity of the different methods to predict close contacts in the representative X-ray structures of an additional 150 protein families using only experimental MSAs. CONCLUSIONS/SIGNIFICANCE: Methods based on the identification of global correlations between pairs were found to be generally superior to methods based only on local correlations in their capacity to identify coevolving residues using either simulated or experimental MSAs. However, the significant variability in the performance of different methods with different proteins suggests that the simulation of MSAs that replicate the statistical properties of the experimental MSA can be a valuable tool to identify the coevolution detection method that is most effective in each case.

Morcos et al. (2011) Direct-coupling analysis of residue coevolution captures native contacts across many protein families. Proc Natl Acad Sci U.S.A 108:E1293-301. (pmid: 22106262)

[ PubMed ] [ DOI ] Abstract The similarity in the three-dimensional structures of homologous proteins imposes strong constraints on their sequence variability. It has long been suggested that the resulting correlations among amino acid compositions at different sequence positions can be exploited to infer spatial contacts within the tertiary protein structure. Crucial to this inference is the ability to disentangle direct and indirect correlations, as accomplished by the recently introduced direct-coupling analysis (DCA). Here we develop a computationally efficient implementation of DCA, which allows us to evaluate the accuracy of contact prediction by DCA for a large number of protein domains, based purely on sequence information. DCA is shown to yield a large number of correctly predicted contacts, recapitulating the global structure of the contact map for the majority of the protein domains examined. Furthermore, our analysis captures clear signals beyond intradomain residue contacts, arising, e.g., from alternative protein conformations, ligand-mediated residue couplings, and interdomain interactions in protein oligomers. Our findings suggest that contacts predicted by DCA can be used as a reliable guide to facilitate computational predictions of alternative protein conformations, protein complex formation, and even the de novo prediction of protein domain structures, contingent on the existence of a large number of homologous sequences which are being rapidly made available due to advances in genome sequencing.

Clark et al. (2011) Using coevolution to predict protein-protein interactions. Methods Mol Biol 781:237-56. (pmid: 21877284)

[ PubMed ] [ DOI ] Abstract Bioinformatic methods to predict protein-protein interactions (PPI) via coevolutionary analysis have -positioned themselves to compete alongside established in vitro methods, despite a lack of understanding for the underlying molecular mechanisms of the coevolutionary process. Investigating the alignment of coevolutionary predictions of PPI with experimental data can focus the effective scope of prediction and lead to better accuracies. A new rate-based coevolutionary method, MMM, preferentially finds obligate interacting proteins that form complexes, conforming to results from studies based on coimmunoprecipitation coupled with mass spectrometry. Using gold-standard databases as a benchmark for accuracy, MMM surpasses methods based on abundance ratios, suggesting that correlated evolutionary rates may yet be better than coexpression at predicting interacting proteins. At the level of protein domains, -coevolution is difficult to detect, even with MMM, except when considering small-scale experimental data involving proteins with multiple domains. Overall, these findings confirm that coevolutionary -methods can be confidently used in predicting PPI, either independently or as drivers of coimmunoprecipitation experiments.

Rodionov et al. (2011) A new, fast algorithm for detecting protein coevolution using maximum compatible cliques. Algorithms Mol Biol 6:17. (pmid: 21672226)

[ PubMed ] [ DOI ] Abstract BACKGROUND: The MatrixMatchMaker algorithm was recently introduced to detect the similarity between phylogenetic trees and thus the coevolution between proteins. MMM finds the largest common submatrices between pairs of phylogenetic distance matrices, and has numerous advantages over existing methods of coevolution detection. However, these advantages came at the cost of a very long execution time. RESULTS: In this paper, we show that the problem of finding the maximum submatrix reduces to a multiple maximum clique subproblem on a graph of protein pairs. This allowed us to develop a new algorithm and program implementation, MMMvII, which achieved more than 600× speedup with comparable accuracy to the original MMM. CONCLUSIONS: MMMvII will thus allow for more more extensive and intricate analyses of coevolution. AVAILABILITY: An implementation of the MMMvII algorithm is available at: http://www.uhnresearch.ca/labs/tillier/MMMWEBvII/MMMWEBvII.php.

Kolesov & Mirny (2009) Using evolutionary information to find specificity-determining and co-evolving residues. Methods Mol Biol 541:421-48. (pmid: 19381538)

[ PubMed ] [ DOI ] Abstract Intricate networks of protein interactions rely on the ability of a protein to recognize its targets: other proteins, ligands, and sites on DNA and RNA. To recognize other molecules, it was suggested that a protein uses a small set of specificity-determining residues (SDRs). How can one find these residues in proteins and distinguish them from other functionally important amino acids? A number of bioinformatics methods to predict SDRs have been developed in recent years. These methods use genomic information and multiple sequence alignments to identify positions exhibiting a specific pattern of conservation and variability. The challenge is to delineate the evolutionary pattern of SDRs from that of the active site residues and the residues responsible for formation of the protein's structure. The phylogenetic history of a protein family makes such analysis particularly hard. Here we present two methods for finding the SDRs and the co-evolving residues (CERs) in proteins. We use a Monte Carlo approach for statistical inference, allowing us to reveal specific evolutionary patterns of SDRs and CERs. We apply these methods to study specific recognition in the bacterial two-component system and in the class Ia aminoacyl-tRNA synthetases. Our results agree well with structural information and the experimental analyses of these systems. Our results point at the complex and distinct patterns characteristic of the evolution of specificity in these systems.

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mfDCA (mean field Direct Coupling Analysis - a recent formulation of a statistical inference framework used to infer direct co-evolutionary couplings among residue pairs in multiple sequence alignments.