Detection of conserved physico-chemical characteristics of
  proteins by analyzing clusters of positions with co-ordinated
  substitutions

Afonnikov, D. A.; Oshchepkov, Dmitry; Колчанов, Н. А.

doi:10.1093/bioinformatics/17.11.1035

Cited by 32 publications

(18 citation statements)

References 44 publications

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“…M was set to half of the sequence length L. Compensatory mutations analysis. Compensatory mutations were analyzed by assigning a scalar metric to each type of amino acid and calculating correlation coefficients of these quantities between different positions of the interacting proteins as introduced in different studies (28,37). By considering a physicochemical amino acid property f, compensatory mutations between two positions i and j were calculated by using the formula r ij ϭ s ij ͱs ii ⅐s jj…”

Section: Scoring Complexes By Using Coevolution Analyses Correlated mentioning

confidence: 99%

Coevolution at protein complex interfaces can be detected by the complementarity trace with important impact for predictive docking

Madaoui

Guérois

2008

Proc. Natl. Acad. Sci. U.S.A.

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Protein surfaces are under significant selection pressure to maintain interactions with their partners throughout evolution. Capturing how selection pressure acts at the interfaces of proteinprotein complexes is a fundamental issue with high interest for the structural prediction of macromolecular assemblies. We tackled this issue under the assumption that, throughout evolution, mutations should minimally disrupt the physicochemical compatibility between specific clusters of interacting residues. This constraint drove the development of the so-called Surface COmplementarity Trace in Complex History score (SCOTCH), which was found to discriminate with high efficiency the structure of biological complexes. SCOTCH performances were assessed not only with respect to other evolution-based approaches, such as conservation and coevolution analyses, but also with respect to statistically based scoring methods. Validated on a set of 129 complexes of known structure exhibiting both permanent and transient intermolecular interactions, SCOTCH appears as a robust strategy to guide the prediction of protein-protein complex structures. Of particular interest, it also provides a basic framework to efficiently track how protein surfaces could evolve while keeping their partners in contact.evolution ͉ prediction ͉ protein-protein interaction T he modular assembly of proteins is a key determinant in the regulation of biological systems. Combinations of inter-and intramolecular interactions hold the cell machineries and govern the flow of information transmitted through cell signaling pathways. To unravel the complexity of cell organization, atlases of the physical interactome have been obtained for several model organisms (1, 2). To further elucidate the competitions and synergies ruling the molecular logic of these protein-protein interaction networks, a critical step relies on the structural characterization of the protein complexes. However, there is still a huge gap between the proteome-wide data accumulating and the available structural details of macromolecular complexes.A number of studies have tackled the large-scale analysis of protein-protein complexes from a structural perspective (3-7). They have emphasized that size, shape, and the physicochemical complementarities at the interfaces are key descriptors that could be used to develop computational methods able to predict protein-binding sites from sequences or structures (8)(9)(10)(11)(12)(13)(14). In the context of evolution, seminal studies compared the binding modes of domain-domain interactions between homologous proteins and concluded that they tend to interact similarly, even if sequence identity has been maintained as low as 30% (15, 16). Such a low conservation threshold suggests that interaction surfaces can evolve significantly while maintaining sufficient specificity between the binding partners. The paradox between sequence divergence and structural conservation of macromolecular assemblies has been recently related to the notion of superfamily, and the exis...

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Section: Scoring Complexes By Using Coevolution Analyses Correlated mentioning

confidence: 99%

Coevolution at protein complex interfaces can be detected by the complementarity trace with important impact for predictive docking

Madaoui

Guérois

2008

Proc. Natl. Acad. Sci. U.S.A.

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“…In the last case, a compensatory mutation often acts to replace the functional role that was disrupted by the preceding amino acid substitution (e.g., residue volume compensation in T4 lysozyme; Baldwin et al 1996). Many studies have therefore attempted to identify the common functional constraints that predict which amino acids will coevolve in a given protein (Altschuh et al 1988;Neher 1994;Shinyalov et al 1994;Azarya-Sprinzak et al 1997;Afonnikov et al 2001;Fukami-Kobayashi et al 2002). This effort is often directed toward the prediction of secondary protein structures from amino acid sequences (e.g., Gö bel et al 1994).…”

Section: Implications Of Biochemical Constraintsmentioning

confidence: 99%

“…Amino acid biochemistry was previously established as a potentially important determinant of compensatory interactions between mutations (Altschuh et al 1988;Azarya-Sprinzak et al 1997;Afonnikov et al 2001). For example, a destabilizing mutation in the bacteriophage T4 lysozyme protein causes a buried residue to be replaced by a smaller amino acid, which can subsequently be compensated by a substitution at an adjacent site for a larger amino acid (Baldwin et al 1996).…”

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confidence: 99%

Functional Origins of Fitness Effect-Sizes of Compensatory Mutations in the Dna Bacteriophage Øx174

Poon

Chao

2006

Evolution

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Abstract. Epistasis is an important and poorly understood aspect of mutations and strongly influences the evolutionary impact of genetic variation on adaptation and fitness. Although recent studies have begun to characterize the distribution of epistatic effects between mutations affecting fitness, there is currently a lack of empirical information on the underlying biological causes of these epistatic interactions. What are the functional constraints that determine the effectiveness of a compensatory mutation at restoring fitness? We have measured the effect-sizes of 52 compensatory mutations affecting nine different deleterious mutations in the major capsid and spike proteins of the DNA bacteriophage X174. On average, an experimentally detectable compensatory mutation recovers about two-thirds of the fitness cost of the preceding deleterious mutation. Variation in fitness effect-sizes is only weakly associated with measures of the distance separating the deleterious and compensatory mutations in the amino acid sequence or the folded protein structure. However, there is a strong association of fitness effect-size with the correlation in the effects of the mutations on the biochemical properties of amino acids. A compensatory mutation has the largest effect-size, on average, when both the compensatory and deleterious mutations have radical effects on the overall biochemical make-up of the amino acids. By examining the relative contributions of specific biochemical properties to variation in fitness effect-size, we find that the area and charge of amino acids have a major influence, which suggests that the complexity of the amino acid phenotype is simplified by selection into a reduced number of phenotypic components.

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“…Nevertheless, healthy mice (and rats) carry Thr at the homologous site of their ␣-synucleins (8). We call such a situation a compensated pathogenic deviation (CPD), because high fitness of this Thr in mice must be due to some other, compensatory difference of mice from humans (10), either within or outside ␣-synuclein. Together, a CPD and the corresponding compensatory change form a DobzhanskyMuller (DM) incompatibility (11,12) (Fig.…”

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confidence: 99%

Dobzhansky–Muller incompatibilities in protein evolution

Kondrashov

Sunyaev

Kondrashov

2002

Proc. Natl. Acad. Sci. U.S.A.

286

358

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We study fitness landscape in the space of protein sequences by relating sets of human pathogenic missense mutations in 32 proteins to amino acid substitutions that occurred in the course of evolution of these proteins. On average, Ϸ10% of deviations of a nonhuman protein from its human ortholog are compensated pathogenic deviations (CPDs), i.e., are caused by an amino acid substitution that, at this site, would be pathogenic to humans. Normal functioning of a CPD-containing protein must be caused by other, compensatory deviations of the nonhuman species from humans. Together, a CPD and the corresponding compensatory deviation form a Dobzhansky-Muller incompatibility that can be visualized as the corner on a fitness ridge. Thus, proteins evolve along fitness ridges which contain only Ϸ10 steps between successive corners. The fraction of CPDs among all deviations of a protein from its human ortholog does not increase with the evolutionary distance between the proteins, indicating that substitutions that carry evolving proteins around these corners occur in rapid succession, driven by positive selection. Data on fitness of interspecies hybrids suggest that the compensatory change that makes a CPD fit usually occurs within the same protein. Data on protein structures and on cooccurrence of amino acids at different sites of multiple orthologous proteins often make it possible to provisionally identify the substitution that compensates a particular CPD.E volution unfolds on a fitness landscape, a map that relates fitness to the genotype (1). Obviously, most of possible genotypes are always unfit, and some of rare fit genotypes must be arranged in continuous ridges (networks). This general paradigm can be applied, inter alia, to the evolution of proteins. ''If evolution . . . is to occur, functional proteins must form a continuous network which can be traversed by unit mutational steps without passing through non-functional intermediates'' (2). However, data on fitness landscapes are limited, because only a tiny fraction of all possible genotypes is actually available, and inferring fitness of currently nonexisting genotypes is difficult (3-6). Relating data on human pathogenic missense mutations, which represent unfit genotypes, to interspecies differences between homologous proteins, all of which must be fit, offers a novel opportunity to probe the fitness landscape in the space of proteins.Human pathogenic amino acid substitutions tend to occur at less variable sites of proteins (7). Thus, an amino acid that in a nonhuman protein is different from the amino acid at the homologous site of the human ortholog would probably be benign for humans if placed into this site. Still, exceptions to this rule have been described (8, 9).For example, the 53rd site of human ␣-synuclein is normally occupied by Ala, and Ala 3 Thr substitution at this site predisposes to Parkinson's disease. Nevertheless, healthy mice (and rats) carry Thr at the homologous site of their ␣-synucleins (8). We call such a situation a compensated pathog...

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Detection of conserved physico-chemical characteristics of proteins by analyzing clusters of positions with co-ordinated substitutions

Abstract: The program package is available at http://wwwmgs.bionet.nsc.ru/programs/CRASP/.

Cited by 32 publications

References 44 publications

Coevolution at protein complex interfaces can be detected by the complementarity trace with important impact for predictive docking

Coevolution at protein complex interfaces can be detected by the complementarity trace with important impact for predictive docking

Functional Origins of Fitness Effect-Sizes of Compensatory Mutations in the Dna Bacteriophage Øx174

Dobzhansky–Muller incompatibilities in protein evolution

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