Ligand binding and circular permutation modify residue interaction network in DHFR.

in PLoS computational biology (2007), 3(6), 117

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 ... [more ▼]

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. [less ▲]

Modular architecture of protein structures and allosteric communications: potential implications for signaling proteins and regulatory linkages.

in Genome biology (2007), 8(5), 92

BACKGROUND: Allosteric communications are vital for cellular signaling. Here we explore a relationship between protein architectural organization and shortcuts in signaling pathways. RESULTS: We show that ... [more ▼]

BACKGROUND: Allosteric communications are vital for cellular signaling. Here we explore a relationship between protein architectural organization and shortcuts in signaling pathways. RESULTS: 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. CONCLUSION: 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. [less ▲]

Residues crucial for maintaining short paths in network communication mediate signaling in proteins.

in Molecular systems biology (2006), 2

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 ... [more ▼]

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. [less ▲]

A framework for computational and experimental methods: identifying dimerization residues in CCR chemokine receptors.

in Bioinformatics (2005), 21 Suppl 2

Solving relevant biological problems requires answering complex questions. Addressing such questions traditionally implied the design of time-consuming experimental procedures which most of the time are ... [more ▼]

Solving relevant biological problems requires answering complex questions. Addressing such questions traditionally implied the design of time-consuming experimental procedures which most of the time are not accessible to average-sized laboratories. The current trend is to move towards a multidisciplinary approach integrating both theoretical knowledge and experimental work. This combination creates a powerful tool for shedding light on biological problems. To illustrate this concept, we present here a descriptive example of where computational methods were shown to be a key aspect in detecting crucial players in an important biological problem: the dimerization of chemokine receptors. Using evolutionary based sequence analysis in combination with structural predictions two CCR5 residues were selected as important for dimerization and further validated experimentally. The experimental validation of computational procedures demonstrated here provides a wealth of valuable information not obtainable by any of the individual approaches alone. [less ▲]

Small-world network approach to identify key residues in protein-protein interaction.

in Proteins (2005), 58(3), 672-82

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 ... [more ▼]

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. [less ▲]

Automatic methods for predicting functionally important residues.

in Journal of molecular biology (2003), 326(4), 1289-302

Sequence analysis is often the first guide for the prediction of residues in a protein family that may have functional significance. A few methods have been proposed which use the division of protein ... [more ▼]

Sequence analysis is often the first guide for the prediction of residues in a protein family that may have functional significance. A few methods have been proposed which use the division of protein families into subfamilies in the search for those positions that could have some functional significance for the whole family, but at the same time which exhibit the specificity of each subfamily ("Tree-determinant residues"). However, there are still many unsolved questions like the best division of a protein family into subfamilies, or the accurate detection of sequence variation patterns characteristic of different subfamilies. Here we present a systematic study in a significant number of protein families, testing the statistical meaning of the Tree-determinant residues predicted by three different methods that represent the range of available approaches. The first method takes as a starting point a phylogenetic representation of a protein family and, following the principle of Relative Entropy from Information Theory, automatically searches for the optimal division of the family into subfamilies. The second method looks for positions whose mutational behavior is reminiscent of the mutational behavior of the full-length proteins, by directly comparing the corresponding distance matrices. The third method is an automation of the analysis of distribution of sequences and amino acid positions in the corresponding multidimensional spaces using a vector-based principal component analysis. These three methods have been tested on two non-redundant lists of protein families: one composed by proteins that bind a variety of ligand groups, and the other composed by proteins with annotated functionally relevant sites. In most cases, the residues predicted by the three methods show a clear tendency to be close to bound ligands of biological relevance and to those amino acids described as participants in key aspects of protein function. These three automatic methods provide a wide range of possibilities for biologists to analyze their families of interest, in a similar way to the one presented here for the family of proteins related with ras-p21. [less ▲]

Connection between type A and E factorizations and construction of satellite algebras

in Journal of Physics: A Mathematical and General (2000)

Generalized Morse potential: Symmetry and satellite potentials

in Journal of Physics: A Mathematical and General (1998)

Ordering problems in fermionic relativistic quantum mechanics

in International Journal of Modern Physics A (1997)

The dirac oscillator of arbitrary spin

in Journal of Physics: A Mathematical and General (1996)