A quantitative analysis of secondary RNA structure using domination based parameters on trees
- Teresa Haynes^{1},
- Debra Knisley^{1}Email author,
- Edith Seier^{1} and
- Yue Zou^{2}
https://doi.org/10.1186/1471-2105-7-108
© Haynes et al; licensee BioMed Central Ltd. 2006
Received: 20 October 2005
Accepted: 03 March 2006
Published: 03 March 2006
Abstract
Background
It has become increasingly apparent that a comprehensive database of RNA motifs is essential in order to achieve new goals in genomic and proteomic research. Secondary RNA structures have frequently been represented by various modeling methods as graph-theoretic trees. Using graph theory as a modeling tool allows the vast resources of graphical invariants to be utilized to numerically identify secondary RNA motifs. The domination number of a graph is a graphical invariant that is sensitive to even a slight change in the structure of a tree. The invariants selected in this study are variations of the domination number of a graph. These graphical invariants are partitioned into two classes, and we define two parameters based on each of these classes. These parameters are calculated for all small order trees and a statistical analysis of the resulting data is conducted to determine if the values of these parameters can be utilized to identify which trees of orders seven and eight are RNA-like in structure.
Results
The statistical analysis shows that the domination based parameters correctly distinguish between the trees that represent native structures and those that are not likely candidates to represent RNA. Some of the trees previously identified as candidate structures are found to be "very" RNA like, while others are not, thereby refining the space of structures likely to be found as representing secondary RNA structure.
Conclusion
Search algorithms are available that mine nucleotide sequence databases. However, the number of motifs identified can be quite large, making a further search for similar motif computationally difficult. Much of the work in the bioinformatics arena is toward the development of better algorithms to address the computational problem. This work, on the other hand, uses mathematical descriptors to more clearly characterize the RNA motifs and thereby reduce the corresponding search space. These preliminary findings demonstrate that graph-theoretic quantifiers utilized in fields such as computer network design hold significant promise as an added tool for genomics and proteomics.
Background
Predicting the final fold of RNA from its sequence is a challenging problem, but has played a secondary role to the protein structure prediction problem. Interest in both the prediction of secondary and tertiary RNA structure is currently gaining substantial momentum. Recently, the Journal Science devoted a special issue to the form and function of RNA [1]. It is now known that RNA is involved in a large variety of processes, including gene regulation. Despite this, the important task of classifying RNA molecules in order to identify structural motifs remains far from complete. Many classes of RNA molecules are characterized by highly conserved secondary structures. Since RNA molecules maintain independently stable and highly conserved secondary folds, RNA function is also highly correlated with its secondary structure. Thus, we focus on identifying structural characteristics of secondary RNA.
The utility of graphs as models of proteins and nucleic acids is fertile ground for the discovery of new and innovative methods for the numerical characterization of biomolecules. In this paper we address the applicability of graphs in the analysis of secondary RNA structure. A mathematical graph, or simply a graph, is a set of points, called vertices, and connecting lines, called edges. Trees are a familiar example of graphs since they are used extensively to aid in phylogenetic studies. RNA tree graphs were first developed by Le et al.[2] and Benededetti and Morosetti[3] to determine structural similarities in RNA. Secondary structure tree representation can also be found in Waterman's classic text, An Introduction to Computational Biology[4]. In a recent paper titled Exploring the repertoire of RNA secondary motifs using graph theory; implications for RNA design, researchers led by Tamar Schlick developed a new method for representing secondary RNA structure as a two dimensional RNA tree graph[5]. Unlike the classic model developed by Waterman et.al. where atoms are represented by vertices and bonds between the atoms by edges in the graph, the RAG (RNA as Graphs) project represents stems as edges and breaks in the stems that result in bulges and loops as vertices. A nucleotide bulge, hairpin loop or internal loop are each represented by a vertex when there is more than one unmatched nucleotide or non-complementary base pair. This modeling method is illustrated in figures 8 and 9. Their method has led to the creation of an RNA topology database called RAG (Rna As Graphs) that is published and available at BMC Bioinformatics and Bioinformatics[6, 7]. In this database, all possible unlabeled trees of a given order (number of vertices) are presented for orders two through eleven. For trees of order eight and below, a color scheme is used; red trees represent a known native secondary RNA structure, blue trees are listed as likely candidates and black trees are those structures that are considered not likely to be found as RNA structures. For trees of order nine and above, blue is not utilized. That is, the likely candidates are not identified. In this work we demonstrate that a graphical analysis of the trees that have been classified by the color scheme, without the aid of thermodynamic properties of the nucleic acids or other biophysical considerations, can determine which trees are RNA-like in structure.
The total number of possible RNA tree graphs for a given number of vertices is given by the tree enumeration theorems of Harary and Prins[8]. Schlick et al.[5] found that existing RNA classes represent only a small subset of the possible tree representations of two-dimensional RNA motifs. It is believed that many more will either be found as a native structure, or synthetically developed. Thus, investigating the quantitative properties of the trees not known to exist as native structures is a natural way to proceed. In a successive paper by the Schlick group, candidates for novel RNA topologies where identified [9]. The RAG project uses two representations for secondary RNA; trees as described above, and dual graphs which we have not discussed here. In [8], dual graphs are used in the analysis and in this work, we analyze the tree graphs. Dual graphs have the advantage in that all secondary RNA structures have a dual graph representation, whereas only certain RNA structures can be represented as a tree. However, part of the purpose of this work is to test the applicability of the enormous amount of graphical invariants available that might aid in the quantification of biomolecules. This work demonstrates the potential for this line of investigation and in fact shows that invariants used in network design and fault-tolerant computing lend themselves to a quantitative analysis of secondary RNA structures.
Results
Graph-theoretic analysis
Statistical results
Status and prediction for trees with seven and eight vertices
Vertices | ID | P _{1} | P _{2} | ${P}_{2}^{*}$ | P(Native) model 1 | P(Native) model 2 | RAG Status | Domination Predicted status |
---|---|---|---|---|---|---|---|---|
7 | 1 | 1.57143 | 1.00000 | 8.3867 | 1.00000 | 1.00000 | native | native |
7 | 2 | 1.28571 | 1.28571 | 10.5778 | 0.99898 | 0.99991 | native | native |
7 | 3 | 1.42857 | 1.00000 | 8.8221 | 1.00000 | 1.00000 | native | native |
7 | 4 | 1.14286 | 1.28571 | 10.8753 | 0.00040 | 0.00392 | candidate | not RNA like |
7 | 5 | 1.28571 | 1.28571 | 11.0685 | 0.99951 | 0.99991 | candidate | native |
7 | 6 | 1.28571 | 1.14286 | 10.2519 | 0.99834 | 0.99908 | native | native |
7 | 7 | 1.28571 | 1.14286 | 10.6740 | 0.99911 | 0.99908 | candidate | native |
7 | 8 | 1.57143 | 1.00000 | 9.6740 | 1.00000 | 1.00000 | candidate | native |
7 | 9 | 1.00000 | 1.42857 | 12.7881 | 0.00000 | 0.00000 | not RNA like | not RNA like |
7 | 10 | 1.00000 | 1.42857 | 13.2613 | 0.00000 | 0.00000 | not RNA like | not RNA like |
7 | 11 | 1.00000 | 1.71429 | 19.0000 | 0.00002 | 0.00000 | not RNA like | not RNA like |
8 | 1 | 1.37500 | 1.12500 | 10.2176 | 1.00000 | 1.00000 | candidate | native |
8 | 2 | 1.37500 | 1.12500 | 10.3336 | 1.00000 | 1.00000 | candidate | native |
8 | 3 | 1.37500 | 1.12500 | 10.4912 | 1.00000 | 1.00000 | native | native |
8 | 4 | 1.25000 | 1.25000 | 11.4912 | 0.98853 | 0.99359 | candidate | native |
8 | 5 | 1.50000 | 1.00000 | 9.5848 | 1.00000 | 1.00000 | native | native |
8 | 6 | 1.25000 | 1.25000 | 11.6184 | 0.99049 | 0.99359 | candidate | native |
8 | 7 | 1.37500 | 1.12500 | 10.7096 | 1.00000 | 1.00000 | native | native |
8 | 8 | 1.25000 | 1.12500 | 10.7944 | 0.96824 | 0.95104 | candidate | native |
8 | 9 | 1.12500 | 1.37500 | 12.9072 | 0.00124 | 0.00269 | not RNA like | not RNA like |
8 | 10 | 1.50000 | 1.12500 | 10.9472 | 1.00000 | 1.00000 | native | native |
8 | 11 | 1.50000 | 1.00000 | 10.0072 | 1.00000 | 1.00000 | native | native |
8 | 12 | 1.37500 | 1.12500 | 11.0304 | 1.00000 | 1.00000 | candidate | native |
8 | 13 | 1.12500 | 1.25000 | 12.1432 | 0.00040 | 0.00034 | candidate | not RNA like |
8 | 14 | 1.12500 | 1.37500 | 13.2192 | 0.00196 | 0.00269 | not RNA like | not RNA like |
8 | 15 | 1.25000 | 1.25000 | 12.3104 | 0.99659 | 0.99359 | native | native |
8 | 16 | 1.37500 | 1.12500 | 11.4520 | 1.00000 | 1.00000 | candidate | native |
8 | 17 | 1.12500 | 1.25000 | 12.5496 | 0.00073 | 0.00034 | not RNA like | not RNA like |
8 | 18 | 1.00000 | 1.50000 | 14.8336 | 0.00000 | 0.00000 | not RNA like | not RNA like |
8 | 19 | 0.87500 | 1.50000 | 14.9904 | 0.00000 | 0.00000 | not RNA like | not RNA like |
8 | 20 | 1.50000 | 1.00000 | 11.0560 | 1.00000 | 1.00000 | native | native |
8 | 21 | 1.12500 | 1.25000 | 13.0560 | 0.00154 | 0.00034 | not RNA like | not RNA like |
8 | 22 | 1.00000 | 1.50000 | 15.6200 | 0.00000 | 0.00000 | not RNA like | not RNA like |
8 | 23 | 0.87500 | 1.75000 | 22.0000 | 0.00000 | 0.00000 | not RNA like | not RNA like |
Discussion
RNA motifs
The RAG database classifies all possible tree structures with eight or fewer vertices as either native structures that have been found, candidate RNAs or non RNA-like in structure. Those that are RNA-like in structure that have not been verified as existing are considered candidates that may later be identified or artificially produced. In this study, we consider all of the tree structures with seven or eight vertices. Using the graphical parameters P_{1}, P_{2} and ${P}_{2}^{*}$, our findings are consistent with the database. That is, the domination based parameters used in the logistic models identify two clusters. All of the native structures and almost all of the RAG candidate structures are predicted as RNA-like by our model and the structures identified by RAG as not RNA-like are also not RNA-like by our models. We also conclude that the tree labeled 8.16 is an exceptionally good candidate while the model rejects trees 7.4 and 8.13 (figure 1b). The emerging area of RNA as a tool and target has produced a wealth of new and innovative pharmaceutical applications. Chemically synthesized RNA's have been produced to aid in the development of novel therapeutics. Functional clusters of RNA, both mRNA and regulatory RNA binding proteins are a rich source of therapeutic tools for the management and potential cures of human disease. This novel approach for identifying tree structures that have definite RNA-like characteristics shows promise as an added tool for the design and analysis of nucleic acids.
Graphs as mathematical objects
- 1.
any vertex outside the set must be adjacent to at least one in the locating-dominating set.
- 2.
given a a single vertex outside the dominating set, the set of vertices in the locating-dominating set that this single vertex is adjacent to is always unique.
If we think of two vertices in the tree as regions in the RNA structure where interaction is most likely to occur due to the fact that there are unpaired nucleotide bases, then if an "interaction" occurs, a mechanism is in place that makes it is possible to discern the location of the interacting region. Graphs have been used extensively to aid in the design and analysis of algorithms and hence are an integral part of the field of bioinformatics [11–13]. However, the use of graphs as the biomolecules themselves has been fairly limited. There have been some earlier models of biomolecules as graphs, but in those cases the graph's spectrum is the primary focus of the analysis[14–16]. For a nice survey on some of the applications see graphs and proteins see[17]. Spectral graph theory has been a useful tool for chemist who have used graphs to model molecules. And other graph theoretic measures have been defined that are well suited for molecular description in the spirit of chemical graph theory[18]. However, the field of graph theory offers many other tools and techniques for further quantification and analysis of graphs. In this work, we show that graphical invariants, which aid in the optimization of computer and electrical networks, are a remarkable new source of information about the structure of secondary RNA molecules.
Conclusion
We have demonstrated that graphical invariants based on domination numbers can numerically identify characteristics of secondary RNA structure. Search algorithms such as RNAMotif[19] can be used to mine nucleotide sequence databases for motifs. RNAMotif allows users to identify similar motifs within the database. However, when the constraints are relaxed to provide more flexibility, the number of motifs identified by the algorithm may become very large. Exhaustive methods to search for similar RNA structure over these large search spaces are likely to be computationally intractable. Much of the work in the bioinformatics arena is toward the development of better algorithms to address the computational problem. This work, on the other hand, uses mathematical descriptors that can easily and more clearly characterize the RNA motifs and thereby significantly reduce the corresponding search space. The graphical invariants used to identify structural characteristics of a class of biomolecules depends on the corresponding graph. By representing biomolecules as graphs, we can then thoroughly investigate the graph using the appropriate graphical invariants; thereby quantifying the structure. Although determining graphical invariants in general is computationally difficult as well, for special classes of graphs such as trees there exist fast algorithms for their computation. These preliminary findings from this novel approach are intriguing and the method shows promise as an added tool for genomic and proteomic prediction tools.
Methods
Graph theory definitions and terminology
Trees have been highly studied as a family of graphs. Therefore, in this work, we employ graphical invariants that are indicative of variations in the structure of trees. In particular, we utilize a number of domination parameters that are highly sensitive to the structural changes of small ordered trees. First we define the graphical invariants that are utilized in this work. These definitions can be found in Fundamentals of Domination in Graphs, Chemical Graph Theory or in Graph Theory and its Applications [10, 20, 21] We denote the vertex set of a graph by V(G), or simply V. The number of edges incident to a vertex v is the degree of the vertex deg(v) and two vertices are adjacent if they are incident to the same edge. A vertex set S is a dominating set if for every vertex u ∈ V - S, u is adjacent to at least one vertex in S. The domination number γ(G) is the minimum cardinality among all dominating sets in G. A set S is a total dominating set if for every vertex u ∈ V, u is adjacent to at least one vertex in S (note here that even the vertices in S must be adjacent to a vertex in S). The total domination number γ_{ t }(G) is the minimum cardinality among all total dominating sets in G. The neighborhood of a vertex v, denoted by N(v), is the set of all vertices adjacent to v and the closed neighborhood of a vertex u is N[u] = N(u) ∪ {u}. A dominating set S is called a locating-dominating set if for any two vertices v, w ∈ V - S, N(v) ∩ S ≠ N(w) ∩ S. Thus, in a locating dominating set, every vertex in V - S is dominated by a distinct subset of the vertices of S. The locating-domination number of a graph G is the minimum cardinality among all locating dominating sets in G and is denoted by γ_{ L }(G). A dominating set S is called a differentiating dominating set if for any two vertices v, w ∈ V, N[v] ∩ S ≠ N[w] ∩ S. The differentiating domination number of a graph G is the minimum cardinality among all differentiating dominating sets in G and is denoted by γ_{ D }(G). The global alliance number of a graph G is the minimum cardinality among all global alliances of G, where a set S is a global alliance if S is a dominating set and for each u ∈ S, the number of "allies" it has in S are at least as many as it has in V - S. In other words, S is a dominating set and for each vertex u ∈ S, it is true that |N[u] ∩ S| ≥ |N(u) ∩ (V - S)|. The adjacency matrix A = A(G) and the degree matrix D = D(G) are the square matrices that contain information about the internal connectivity of vertices in G. They are defined as
${A}_{i,j}=\{\begin{array}{cc}\hfill 1\hfill & \hfill {\text{ifandonlyifv}}_{i}\text{and}{v}_{j}\text{areadjacent}\hfill \\ \hfill 0\hfill & \hfill \text{otherwise}\hfill \end{array}$
${D}_{i,j}=\{\begin{array}{ccc}\hfill deg({v}_{i})\hfill & \hfill \text{if}\hfill & \hfill i=j\hfill \\ \hfill 0\hfill & \hfill \text{otherwise}\hfill \end{array}$
The Laplacian matrix L = L_{ ij }(G) is the square matrix defined by L = D - A
${L}_{ij}=\{\begin{array}{ccc}\hfill deg({v}_{i})\hfill & \hfill \text{if}\hfill & \hfill i=j\hfill \\ \hfill -1\hfill & \hfill \text{if}\hfill & \hfill i\ne j\text{and}({v}_{i},{v}_{j})\in E(G)\hfill \\ \hfill 0\hfill & \hfill \text{otherwise}\hfill \end{array}$
The eigenvalues of the Laplacian matrix of a graph is the graph's spectrum. The eigenvalues are related to the density distribution of the edge set. The second smallest eigenvalue, denoted by λ_{2} (often called the Fiedler eigenvalue) is the best measure of the graph's connectivity among all of the eigenvalues. Large values for λ_{2} correspond to vertices of high degree that are in close proximity whereas small values for λ_{2} correspond to a more equally dispersed edge set.
Domination based parameters
We calculated a number of graphical invariants for each tree and tabulated the results. As in the RAG database, the trees were cataloged by their Fiedler eigenvalues. In so doing, we noticed that the domination parameters behaved in two distinct ways with respect to the Fiedler eigenvalue. The domination, total domination, and global alliance numbers tended to decrease as the eigenvalues increased. The locating-domination and differentiating domination numbers tended to increase as the eigenvalues increased. Thus, we grouped the invariants into two classes and summed the values in each class. To normalize the results, the sums were divided by the total number of vertices in the tree, defining the two parameters P_{1} and P_{2} In the case where the invariants behaved oppositional to the eigenvalues, P_{2} was modified in the following way. Instead of dividing by the total number of vertices in the tree, the Fiedler eigenvalue was multiplied by the number of vertices and included the product in the sum. We denote this parameter by P_{2*}. The three formulas for P_{1}, P_{1}, P_{2} and P_{2*} are given below and are used to complete Table 1.
$\begin{array}{c}{P}_{1}=\frac{\gamma +{\gamma}_{t}+{\gamma}_{a}}{n}\\ {P}_{2}=\frac{{\gamma}_{L}+{\gamma}_{D}}{n}\\ {P}_{2}^{*}={\gamma}_{L}+{\gamma}_{D}+n{\lambda}_{2}\end{array}$
As seen above, P_{1} is the sum of the graphical invariants that tended to decrease as the Fiedler eigenvalues increased. The other case is given by P_{2} and ${P}_{2}^{*}$.
Statistical methods
Logistic models were used to predict the probability that a tree is a native RNA structure based on its domination numbers. Two different logistic models were estimated using SAS, one based on P_{1} and P_{2}(definitions based on domination only) and another one based on P_{1} and ${P}_{2}^{*}$ (that considers domination and the second smallest eigenvalue). Due to the abrupt change from native to not RNA-like for small changes in P_{1} and P_{2} or P_{1} and ${P}_{2}^{*}$, the maximum likelihood estimation process does not converge; however the predicted categories obtained with those models were correct in 100% of the cases considering the 11 trees that are known to exist as RNA structures. The estimated values for the parameters correspond to the last iteration. Logistic models are usually evaluated by the percent of concordant pairs and the percent of correctly predicted values; for the two models the percent of concordant pairs and the percent of correct predictions (for those known to be native or predicted by RAG as 'not RNA-like') is 100%. The two models are:
Model 1 : ln[$\widehat{p}$/(1 - $\widehat{p}$)] = -146.1 + 104.3P_{1} + 16.6148P_{2}
Model 2 : ln[$\widehat{p}$/(1 - $\widehat{p}$)] = -145.3 + 106.1P_{1} + 1.4908${P}_{2}^{*}$
where $\widehat{p}$ is the estimated probability of being native given the values of P_{1} and P_{2} or P_{1} and ${P}_{2}^{*}$. When $\widehat{p}$ > 0.5 the tree is predicted to be native. The values of $\widehat{p}$ obtained with each one of the two models are very similar and therefore the predictions as native or not RNA-like for both models are the same for each the trees. All of the 23 trees whose status is either 'native' or 'RAG predicted not RNA-like' were likewise predicted by the two domination models. From the 4 RAG candidates with 7 vertices (RAG RNA-like, but not yet found as a native structure), 3 are predicted by the domination model as RNA-like and one, (7.4), as non-RNA like. From the 8 candidates with 8 vertices, 7 are predicted to be native and only one, (8.13), is predicted as not RNA-like. Table 1 displays the values of P_{1}, P_{2} and ${P}_{2}^{*}$ for all trees with 7 and 8 vertices. The estimated probability of being native $\widehat{p}$ obtained with each one of the models (ml and m2) and the RAG status are also displayed.
A third model, using P_{1} as sole predictor was also estimated. Again the estimation process does not converge because of the abrupt change and total separation of values; P_{1} < 1.2 for all natives and P_{1} > 1.2 for all not RNA like. The model with the estimates of the last iteration is ln[$\widehat{p}$/(1 - $\widehat{p}$)] = -109.3 + 91.407P_{1} The estimated probabilities P(native) are plotted for a range of values of P_{1} in Figure 7. The class (native or not RNA-like) predicted for the candidates using this model is the same given by the other two models.
Declarations
Acknowledgements
We are indebted to Tamar Schlick and her research group at NYU for the creation of the RAG database. The authors appreciate the efforts of the SUMMA undergraduate research participants Jeremy Smith, Huda Hussein and Tywanna Anderson as well as ETSU graduate students Steve Lane and Travis Coake. The SUMMA-2004 program was supported by NSF:DMS 03538341 and 0337406 and the NSA: H98230-041-0079.
Authors’ Affiliations
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