Publications (13)61.12 Total impact
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Article: The origin of allosteric functional modulation: multiple pre-existing pathways.
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ABSTRACT: Although allostery draws increasing attention, not much is known about allosteric mechanisms. Here we argue that in all proteins, allosteric signals transmit through multiple, pre-existing pathways; which pathways dominate depend on protein topologies, specific binding events, covalent modifications, and cellular (environmental) conditions. Further, perturbation events at any site on the protein surface (or in the interior) will not create new pathways but only shift the pre-existing ensemble of pathways. Drugs binding at different sites or mutational events in disease shift the ensemble toward the same conformations; however, the relative populations of the different states will change. Consequently the observed functional, conformational, and dynamic effects will be different. This is the origin of allosteric functional modulation in dynamic proteins: allostery does not necessarily need to invoke conformational rearrangements to control protein activity and pre-existing pathways are always defaulted to during allostery regardless of the stimulant and perturbation site in the protein.Structure 09/2009; 17(8):1042-50. · 6.35 Impact Factor -
Article: Methyl side-chain dynamics prediction based on protein structure.
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ABSTRACT: Protein dynamics is believed to influence protein function through a variety of mechanisms, some of which are not fully understood. Thus, prediction of protein flexibility from sequence or structural characteristics would assist in comprehension of the ways dynamics is linked to function, and would be important in protein modeling and design. In particular, quantitative description of side-chain dynamics would allow us to understand the role of side-chain flexibility in different functional processes, such as protein-ligand and protein-protein interactions. Using a dataset of 18 proteins, we trained a neural network for the prediction of methyl-bearing side-chain dynamics as described by the methyl side-chain generalized order parameters (S(2)) inferred from NMR data. The network uses 10 input parameters extracted from 3D structures. The average correlation coefficient between the experimental and predicted generalized order parameters is r = 0.71 +/- 0.029. Further analysis revealed that the order parameter depends more strongly on the methyl carbon packing density, the methyl carbon distance to the C(alpha) atom, and the knowledge-based pair-wise contact potential between the methyl carbon and neighboring amino acids. In general, we observed an improvement in the prediction of methyl order parameters by our network in comparison with molecular dynamics simulations. The sensitivity of the predictions to minor structural changes was illustrated in two examples (calmodulin and barnase) by comparing the S(2) predictions for the unbound and ligand-bound structures. The method was able to correctly predict most of the significant changes in side-chain dynamics upon ligand binding, and identified some residues involved in long-range communications or protein-ligand binding. http://epigenomique.genopole.fr/ approximately carbonellBioinformatics 08/2009; 25(19):2552-8. · 5.47 Impact Factor -
Article: Energetic determinants of protein binding specificity: insights into protein interaction networks.
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ABSTRACT: One of the challenges of the postgenomic era is to provide a more realistic representation of cellular processes by combining a systems biology description of functional networks with information on their interacting components. Here we carried out a systematic large-scale computational study on a structural protein-protein interaction network dataset in order to dissect thermodynamic characteristics of binding determining the interplay between protein affinity and specificity. As expected, interactions involving specific binding sites display higher affinities than those of promiscuous binding sites. Next, in order to investigate a possible role of modular distribution of hot spots in binding specificity, we divided binding sites into modules previously shown to be energetically independent. In general, hot spots that interact with different partners are located in different modules. We further observed that common hot spots tend to interact with partners exhibiting common binding motifs, whereas different hot spots tend to interact with partners with different motifs. Thus, energetic properties of binding sites provide insights into the way proteins modulate interactions with different partners. Knowledge of those factors playing a role in protein specificity is important for understanding how proteins acquire additional partners during evolution. It should also be useful in drug design.Proteomics 05/2009; 9(7):1744-53. · 4.43 Impact Factor -
Article: Protein allostery, signal transmission and dynamics: a classification scheme of allosteric mechanisms.
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ABSTRACT: Allostery has come of age; the number, breadth and functional roles of documented protein allostery cases are rising quickly. Since all dynamic proteins are potentially allosteric and allostery plays crucial roles in all cellular pathways, sorting and classifying allosteric mechanisms in proteins should be extremely useful in understanding and predicting how the signals are regulated and transmitted through the dynamic multi-molecular cellular organizations. Classification organizes the complex information thereby unraveling relationships and patterns in molecular activation and repression. In signaling, current classification schemes consider classes of molecules according to their functions; for example, epinephrine and norepinephrine secreted by the central nervous system are classified as neurotransmitters. Other schemes would account for epinephrine when secreted by the adrenal medulla to be hormone-like. Yet, such classifications account for the global function of the molecule; not for the molecular mechanism of how the signal transmission initiates and how it is transmitted. Here we provide a unified view of allostery and the first classification framework. We expect that a classification scheme would assist in comprehension of allosteric mechanisms, in prediction of signaling on the molecular level, in better comprehension of pathways and regulation of the complex signals, in translating them to the cascading events, and in allosteric drug design. We further provide a range of examples illustrating mechanisms in protein allostery and their classification from the cellular functional standpoint.Molecular BioSystems 04/2009; 5(3):207-16. · 3.53 Impact Factor -
Article: Allostery: absence of a change in shape does not imply that allostery is not at play.
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ABSTRACT: Allostery is essential for controlled catalysis, signal transmission, receptor trafficking, turning genes on and off, and apoptosis. It governs the organism's response to environmental and metabolic cues, dictating transient partner interactions in the cellular network. Textbooks taught us that allostery is a change of shape at one site on the protein surface brought about by ligand binding to another. For several years, it has been broadly accepted that the change of shape is not induced; rather, it is observed simply because a larger protein population presents it. Current data indicate that while side chains can reorient and rewire, allostery may not even involve a change of (backbone) shape. Assuming that the enthalpy change does not reverse the free-energy change due to the change in entropy, entropy is mainly responsible for binding.Journal of Molecular Biology 05/2008; 378(1):1-11. · 4.00 Impact Factor -
Article: The modular organization of domain structures: insights into protein-protein binding.
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ABSTRACT: Domains are the building blocks of proteins and play a crucial role in protein-protein interactions. Here, we propose a new approach for the analysis and prediction of domain-domain interfaces. Our method, which relies on the representation of domains as residue-interacting networks, finds an optimal decomposition of domain structures into modules. The resulting modules comprise highly cooperative residues, which exhibit few connections with other modules. We found that non-overlapping binding sites in a domain, involved in different domain-domain interactions, are generally contained in different modules. This observation indicates that our modular decomposition is able to separate protein domains into regions with specialized functions. Our results show that modules with high modularity values identify binding site regions, demonstrating the predictive character of modularity. Furthermore, the combination of modularity with other characteristics, such as sequence conservation or surface patches, was found to improve our predictions. In an attempt to give a physical interpretation to the modular architecture of domains, we analyzed in detail six examples of protein domains with available experimental binding data. The modular configuration of the TEM1-beta-lactamase binding site illustrates the energetic independence of hotspots located in different modules and the cooperativity of those sited within the same modules. The energetic and structural cooperativity between intramodular residues is also clearly shown in the example of the chymotrypsin inhibitor, where non-binding site residues have a synergistic effect on binding. Interestingly, the binding site of the T cell receptor beta chain variable domain 2.1 is contained in one module, which includes structurally distant hot regions displaying positive cooperativity. These findings support the idea that modules possess certain functional and energetic independence. A modular organization of binding sites confers robustness and flexibility to the performance of the functional activity, and facilitates the evolution of protein interactions.PLoS Computational Biology 01/2008; 3(12):e239. · 5.22 Impact Factor -
Article: Ligand binding and circular permutation modify residue interaction network in DHFR.
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ABSTRACT: Residue interaction networks and loop motions are important for catalysis in dihydrofolate reductase (DHFR). Here, we investigate the effects of ligand binding and chain connectivity on network communication in DHFR. We carry out systematic network analysis and molecular dynamics simulations of the native DHFR and 19 of its circularly permuted variants by breaking the chain connections in ten folding element regions and in nine nonfolding element regions as observed by experiment. Our studies suggest that chain cleavage in folding element areas may deactivate DHFR due to large perturbations in the network properties near the active site. The protein active site is near or coincides with residues through which the shortest paths in the residue interaction network tend to go. Further, our network analysis reveals that ligand binding has "network-bridging effects" on the DHFR structure. Our results suggest that ligand binding leads to a modification, with most of the interaction networks now passing through the cofactor, shortening the average shortest path. Ligand binding at the active site has profound effects on the network centrality, especially the closeness.PLoS Computational Biology 07/2007; 3(6):e117. · 5.22 Impact Factor -
Article: Modular architecture of protein structures and allosteric communications: potential implications for signaling proteins and regulatory linkages.
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ABSTRACT: Allosteric communications are vital for cellular signaling. Here we explore a relationship between protein architectural organization and shortcuts in signaling pathways. We show that protein domains consist of modules interconnected by residues that mediate signaling through the shortest pathways. These mediating residues tend to be located at the inter-modular boundaries, which are more rigid and display a larger number of long-range interactions than intra-modular regions. The inter-modular boundaries contain most of the residues centrally conserved in the protein fold, which may be crucial for information transfer between amino acids. Our approach to modular decomposition relies on a representation of protein structures as residue-interacting networks, and removal of the most central residue contacts, which are assumed to be crucial for allosteric communications. The modular decomposition of 100 multi-domain protein structures indicates that modules constitute the building blocks of domains. The analysis of 13 allosteric proteins revealed that modules characterize experimentally identified functional regions. Based on the study of an additional functionally annotated dataset of 115 proteins, we propose that high-modularity modules include functional sites and are the basic functional units. We provide examples (the Galphas subunit and P450 cytochromes) to illustrate that the modular architecture of active sites is linked to their functional specialization. Our method decomposes protein structures into modules, allowing the study of signal transmission between functional sites. A modular configuration might be advantageous: it allows signaling proteins to expand their regulatory linkages and may elicit a broader range of control mechanisms either via modular combinations or through modulation of inter-modular linkages.Genome biology 02/2007; 8(5):R92. · 6.63 Impact Factor -
Article: Residue centrality, functionally important residues, and active site shape: analysis of enzyme and non-enzyme families.
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ABSTRACT: The representation of protein structures as small-world networks facilitates the search for topological determinants, which may relate to functionally important residues. Here, we aimed to investigate the performance of residue centrality, viewed as a family fold characteristic, in identifying functionally important residues in protein families. Our study is based on 46 families, including 29 enzyme and 17 non-enzyme families. A total of 80% of these central positions corresponded to active site residues or residues in direct contact with these sites. For enzyme families, this percentage increased to 91%, while for non-enzyme families the percentage decreased substantially to 48%. A total of 70% of these central positions are located in catalytic sites in the enzyme families, 64% are in hetero-atom binding sites in those families binding hetero-atoms, and only 16% belong to protein-protein interfaces in families with protein-protein interaction data. These differences reflect the active site shape: enzyme active sites locate in surface clefts, hetero-atom binding residues are in deep cavities, while protein-protein interactions involve a more planar configuration. On the other hand, not all surface cavities or clefts are comprised of central residues. Thus, closeness centrality identifies functionally important residues in enzymes. While here we focus on binding sites, we expect to identify key residues for the integration and transmission of the information to the rest of the protein, reflecting the relationship between fold and function. Residue centrality is more conserved than the protein sequence, emphasizing the robustness of protein structures.Protein Science 10/2006; 15(9):2120-8. · 2.80 Impact Factor -
Article: Residues crucial for maintaining short paths in network communication mediate signaling in proteins.
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ABSTRACT: Here, we represent protein structures as residue interacting networks, which are assumed to involve a permanent flow of information between amino acids. By removal of nodes from the protein network, we identify fold centrally conserved residues, which are crucial for sustaining the shortest pathways and thus play key roles in long-range interactions. Analysis of seven protein families (myoglobins, G-protein-coupled receptors, the trypsin class of serine proteases, hemoglobins, oligosaccharide phosphorylases, nuclear receptor ligand-binding domains and retroviral proteases) confirms that experimentally many of these residues are important for allosteric communication. The agreement between the centrally conserved residues, which are key in preserving short path lengths, and residues experimentally suggested to mediate signaling further illustrates that topology plays an important role in network communication. Protein folds have evolved under constraints imposed by function. To maintain function, protein structures need to be robust to mutational events. On the other hand, robustness is accompanied by an extreme sensitivity at some crucial sites. Thus, here we propose that centrally conserved residues, whose removal increases the characteristic path length in protein networks, may relate to the system fragility.Molecular Systems Biology 02/2006; 2:2006.0019. · 8.63 Impact Factor -
Article: Topology of small-world networks of protein-protein complex structures.
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ABSTRACT: The majority of real examples of small-world networks exhibit a power law distribution of edges among the nodes, therefore not fitting into the wiring model proposed by Watts and Strogatz. However, protein structures can be modeled as small-world networks, with a distribution of the number of links decaying exponentially as in the case of this wiring model. We approach the protein-protein interaction mechanism by viewing it as a particular rewiring occurring in the system of two small-world networks represented by the monomers, where a re-arrangement of links takes place upon dimerization leaving the small-world character in the dimer network. Due to this rewiring, the most central residues at the complex interfaces tend to form clusters, which are not homogenously distributed. We show that these highly central residues are strongly correlated with the presence of hot spots of binding free energy. CONTACT: ao-mesa@fujirebio.co.jp SUPPLEMENTARY INFORMATION: http://www.fujirebio.co.jp/support/index.php (under construction).Bioinformatics 05/2005; 21(8):1311-5. · 5.47 Impact Factor -
Article: Small-world network approach to identify key residues in protein-protein interaction.
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ABSTRACT: We show that protein complexes can be represented as small-world networks, exhibiting a relatively small number of highly central amino-acid residues occurring frequently at protein-protein interfaces. We further base our analysis on a set of different biological examples of protein-protein interactions with experimentally validated hot spots, and show that 83% of these predicted highly central residues, which are conserved in sequence alignments and nonexposed to the solvent in the protein complex, correspond to or are in direct contact with an experimentally annotated hot spot. The remaining 17% show a general tendency to be close to an annotated hot spot. On the other hand, although there is no available experimental information on their contribution to the binding free energy, detailed analysis of their properties shows that they are good candidates for being hot spots. Thus, highly central residues have a clear tendency to be located in regions that include hot spots. We also show that some of the central residues in the protein complex interfaces are central in the monomeric structures before dimerization and that possible information relating to hot spots of binding free energy could be obtained from the unbound structures.Proteins Structure Function and Bioinformatics 03/2005; 58(3):672-82. · 3.39 Impact Factor -
Article: Topology of small-world networks of protein?Cprotein complex structures.
Bioinformatics. 01/2005; 21:1311-1315.
