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1.  BalestraWeb: efficient online evaluation of drug–target interactions 
Bioinformatics  2014;31(1):131-133.
Summary: BalestraWeb is an online server that allows users to instantly make predictions about the potential occurrence of interactions between any given drug–target pair, or predict the most likely interaction partners of any drug or target listed in the DrugBank. It also permits users to identify most similar drugs or most similar targets based on their interaction patterns. Outputs help to develop hypotheses about drug repurposing as well as potential side effects.
Availability and implementation: BalestraWeb is accessible at http://balestra.csb.pitt.edu/. The tool is built using a probabilistic matrix factorization method and DrugBank v3, and the latent variable models are trained using the GraphLab collaborative filtering toolkit. The server is implemented using Python, Flask, NumPy and SciPy.
Contact: bahar@pitt.edu
doi:10.1093/bioinformatics/btu599
PMCID: PMC4271144  PMID: 25192741
2.  ProDy: Protein Dynamics Inferred from Theory and Experiments 
Bioinformatics  2011;27(11):1575-1577.
Summary: We developed a Python package, ProDy, for structure-based analysis of protein dynamics. ProDy allows for quantitative characterization of structural variations in heterogeneous datasets of structures experimentally resolved for a given biomolecular system, and for comparison of these variations with the theoretically predicted equilibrium dynamics. Datasets include structural ensembles for a given family or subfamily of proteins, their mutants and sequence homologues, in the presence/absence of their substrates, ligands or inhibitors. Numerous helper functions enable comparative analysis of experimental and theoretical data, and visualization of the principal changes in conformations that are accessible in different functional states. ProDy application programming interface (API) has been designed so that users can easily extend the software and implement new methods.
Availability: ProDy is open source and freely available under GNU General Public License from http://www.csb.pitt.edu/ProDy/.
Contact: ahb12@pitt.edu; bahar@pitt.edu
doi:10.1093/bioinformatics/btr168
PMCID: PMC3102222  PMID: 21471012
4.  Principal component analysis of native ensembles of biomolecular structures (PCA_NEST): insights into functional dynamics 
Bioinformatics  2009;25(5):606-614.
Motivation: To efficiently analyze the ‘native ensemble of conformations’ accessible to proteins near their folded state and to extract essential information from observed distributions of conformations, reliable mathematical methods and computational tools are needed.
Result: Examination of 24 pairs of structures determined by both NMR and X-ray reveals that the differences in the dynamics of the same protein resolved by the two techniques can be tracked to the most robust low frequency modes elucidated by principal component analysis (PCA) of NMR models. The active sites of enzymes are found to be highly constrained in these PCA modes. Furthermore, the residues predicted to be highly immobile are shown to be evolutionarily conserved, lending support to a PCA-based identification of potential functional sites. An online tool, PCA_NEST, is designed to derive the principal modes of conformational changes from structural ensembles resolved by experiments or generated by computations.
Availability: http://ignm.ccbb.pitt.edu/oPCA_Online.htm
Contact: lwy1@iam.u-tokyo.ac.jp
Supplementary information: Supplementary data are available at Bioinformatics online.
doi:10.1093/bioinformatics/btp023
PMCID: PMC2647834  PMID: 19147661
5.  Analysis of correlated mutations in HIV-1 protease using spectral clustering 
Bioinformatics  2008;24(10):1243-1250.
Motivation: The ability of human immunodeficiency virus-1 (HIV-1) protease to develop mutations that confer multi-drug resistance (MDR) has been a major obstacle in designing rational therapies against HIV. Resistance is usually imparted by a cooperative mechanism that can be elucidated by a covariance analysis of sequence data. Identification of such correlated substitutions of amino acids may be obscured by evolutionary noise.
Results: HIV-1 protease sequences from patients subjected to different specific treatments (set 1), and from untreated patients (set 2) were subjected to sequence covariance analysis by evaluating the mutual information (MI) between all residue pairs. Spectral clustering of the resulting covariance matrices disclosed two distinctive clusters of correlated residues: the first, observed in set 1 but absent in set 2, contained residues involved in MDR acquisition; and the second, included those residues differentiated in the various HIV-1 protease subtypes, shortly referred to as the phylogenetic cluster. The MDR cluster occupies sites close to the central symmetry axis of the enzyme, which overlap with the global hinge region identified from coarse-grained normal-mode analysis of the enzyme structure. The phylogenetic cluster, on the other hand, occupies solvent-exposed and highly mobile regions. This study demonstrates (i) the possibility of distinguishing between the correlated substitutions resulting from neutral mutations and those induced by MDR upon appropriate clustering analysis of sequence covariance data and (ii) a connection between global dynamics and functional substitution of amino acids.
Contact: bahar@ccbb.pitt.edu
Supplementary information: Supplementary data are available at Bioinformatics online.
doi:10.1093/bioinformatics/btn110
PMCID: PMC2373918  PMID: 18375964
6.  iGNM: a database of protein functional motions based on Gaussian Network Model 
Bioinformatics (Oxford, England)  2005;21(13):2978-2987.
Motivation
The knowledge of protein structure is not sufficient for understanding and controlling its function. Function is a dynamic property. Although protein structural information has been rapidly accumulating in databases, little effort has been invested to date toward systematically characterizing protein dynamics. The recent success of analytical methods based on elastic network models, and in particular the Gaussian Network Model (GNM), permits us to perform a high-throughput analysis of the collective dynamics of proteins.
Results
We computed the GNM dynamics for 20 058 structures from the Protein Data Bank, and generated information on the equilibrium dynamics at the level of individual residues. The results are stored on a web-based system called i GNM and configured so as to permit the users to visualize or download the results through a standard web browser using a simple search engine. Static and animated images for describing the conformational mobility of proteins over a broad range of normal modes are accessible, along with an online calculation engine available for newly deposited structures. A case study of the dynamics of 20 non-homologous hydrolases is presented to illustrate the utility of the iGNM database for identifying key residues that control the cooperative motions and revealing the connection between collective dynamics and catalytic activity.
Availability
http://ignm.ccbb.pitt.edu/
doi:10.1093/bioinformatics/bti469
PMCID: PMC1752228  PMID: 15860562
7.  Mining frequent patterns in protein structures: a study of protease families 
Bioinformatics (Oxford, England)  2004;20(Suppl 1):i77-i85.
Motivation
Analysis of protein sequence and structure databases usually reveal frequent patterns (FP) associated with biological function. Data mining techniques generally consider the physicochemical and structural properties of amino acids and their microenvironment in the folded structures. Dynamics is not usually considered, although proteins are not static, and their function relates to conformational mobility in many cases.
Results
This work describes a novel unsupervised learning approach to discover FPs in the protein families, based on biochemical, geometric and dynamic features. Without any prior knowledge of functional motifs, the method discovers the FPs for each type of amino acid and identifies the conserved residues in three protease subfamilies; chymotrypsin and subtilisin subfamilies of serine proteases and papain subfamily of cysteine proteases. The catalytic triad residues are distinguished by their strong spatial coupling (high interconnectivity) to other conserved residues. Although the spatial arrangements of the catalytic residues in the two subfamilies of serine proteases are similar, their FPs are found to be quite different. The present approach appears to be a promising tool for detecting functional patterns in rapidly growing structure databases and providing insights in to the relationship among protein structure, dynamics and function.
doi:10.1093/bioinformatics/bth912
PMCID: PMC1201446  PMID: 15262784

Results 1-7 (7)