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Turner B.,Molecular Structure and Function Program
Database : the journal of biological databases and curation | Year: 2010

We present iRefWeb, a web interface to protein interaction data consolidated from 10 public databases: BIND, BioGRID, CORUM, DIP, IntAct, HPRD, MINT, MPact, MPPI and OPHID. iRefWeb enables users to examine aggregated interactions for a protein of interest, and presents various statistical summaries of the data across databases, such as the number of organism-specific interactions, proteins and cited publications. Through links to source databases and supporting evidence, researchers may gauge the reliability of an interaction using simple criteria, such as the detection methods, the scale of the study (high- or low-throughput) or the number of cited publications. Furthermore, iRefWeb compares the information extracted from the same publication by different databases, and offers means to follow-up possible inconsistencies. We provide an overview of the consolidated protein-protein interaction landscape and show how it can be automatically cropped to aid the generation of meaningful organism-specific interactomes. iRefWeb can be accessed at: http://wodaklab.org/iRefWeb. Database URL: http://wodaklab.org/iRefWeb/

Lingwood C.A.,Molecular Structure and Function Program
Discovery medicine | Year: 2011

Much remains unknown about basic aspects of HIV-1 infection and cell susceptibility. Glycosphingolipid (GSL) binding by the HIV-1 adhesin gp120 has long been implicated in the infection of non-lymphoid cells, as well as CD4(+) T cells and monocytes, the primary targets of HIV-1 infection. We have identified the P(k) blood group antigen (a GSL) globotriaosylceramide (Gb(3)) as a new resistance effector against HIV-1 infection. Significantly, the α-galactosyltransferase (A4GALT, Gb(3) synthase) responsible for the synthesis of Gb(3) is included among markers genetically linked to HIV-1 resistance. Other GSLs, including GalCer and GM3, have been implicated as facilitators of HIV infection. This review will address the role of GSLs in HIV/AIDS but focus on the role of Gb(3) as a newly described natural resistance factor for the prevention of HIV infection and examine potential therapies that would utilize soluble analogues of this unique GSL.

Consta S.,University of Western Ontario | Malevanets A.,Molecular Structure and Function Program
Molecular Simulation | Year: 2015

We review recent advances in the understanding of ejection mechanisms of solvated ions and charged macromolecules from highly charged nanodroplets. While the physical basis for the instability leading to droplet fragmentation is relatively well understood, a description of molecular mechanism of the fragmentation in complex systems is still missing. Development of a comprehensive model for the droplet fragmentation is further complicated by chemical modifications of the charged macromolecules (macroions) in a changing droplet environment. We highlight several different molecular simulation techniques used to study fragmentation of charged droplets with different solutes. Ejection of simple ions is analysed using theory of activated processes and transfer reaction coordinate (TRC). The TRC was shown to adequately represent complex rearrangement of solvent molecules in the course of evaporation. The critical value of the square of the charge to volume ratio for spontaneous ejection of simple solvated ions from aqueous droplets is found to be very close to that predicted by Rayleigh's model. On the contrary, the presence of macromolecules adds a level of complexity into the system where the charge-induced instabilities cannot be described by a conventional theory such as Rayleigh or ion-evaporation mechanism. Additional charge-charge interactions between charged sites on a macromolecule dramatically change the macroion ejection mechanism. Molecular dynamics simulations reveal a number of distinct scenarios: contiguous extrusion, drying-out, star-like formation of solvent surrounding a macroion and pearl formation along the macromolecular chain. © 2015 Taylor & Francis.

Consta S.,University of Western Ontario | Malevanets A.,Molecular Structure and Function Program
Journal of Chemical Physics | Year: 2013

The relation between the charge state of a macromolecule and its ejection mechanism from droplets is one of the important questions in electrospray ionization methods. In this article, effects of solvent-solute interaction on the manifestation of the charge induced instability in a droplet are examined. We studied the instabilities in a prototype system of a droplet comprised of charged poly(ethylene glycol) and methanol, acetonitrile, and water solvents. We observed instances of three, previously only conjectured, [S. Consta, J. Phys. Chem. B 114, 5263 (2010)10.1021/jp912119v] mechanisms of macroion ejection. The mechanism of ejection of charged macroion in methanol is reminiscent of "pearl" model in polymer physics. In acetonitrile droplets, the instability manifests through formation of solvent spines around the solvated macroion. In water, we find that the macroion is ejected from the droplet through contiguous extrusion of a part of the chain. The difference in the morphology of the instabilities is attributed to the interplay between forces arising from the macroion solvation energy and the surface energy of the droplet interface. For the contiguous extrusion of a charged macromolecule from a droplet, we demonstrate that the proposed mechanism leads to ejection of the macromolecule from droplets with sizes well below the Rayleigh limit. The ejected macromolecule may hold charge significantly higher than that suggested by prevailing theories. The simulations reveal new mechanisms of macroion evaporation that differ from conventional charge residue model and ion evaporation mechanisms. © 2013 American Institute of Physics.

Lensink M.F.,A+ Network | Lensink M.F.,Free University of Colombia | Wodak S.J.,Molecular Structure and Function Program | Wodak S.J.,University of Toronto
Proteins: Structure, Function and Bioinformatics | Year: 2010

Reliable prediction of the amino acid residues involved in protein-protein interfaces can provide valuable insight into protein function, and inform mutagenesis studies, and drug design applications. A fast-growing number of methods are being proposed for predicting protein interfaces, using structural information, energetic criteria, or sequence conservation or by integrating multiple criteria and approaches. Overall however, their performance remains limited, especially when applied to nonobligate protein complexes, where the individual components are also stable on their own. Here, we evaluate interface predictions derived from protein-protein docking calculations. To this end we measure the overlap between the interfaces in models of protein complexes submitted by 76 participants in CAPRI (Critical Assessment of Predicted Interactions) and those of 46 observed interfaces in 20 CAPRI targets corresponding to nonobligate complexes. Our evaluation considers multiple models for each target interface, submitted by different participants, using a variety of docking methods. Although this results in a substantial variability in the prediction performance across participants and targets, clear trends emerge. Docking methods that perform best in our evaluation predict interfaces with average recall and precision levels of about 60%, for a small majority (60%) of the analyzed interfaces. These levels are significantly higher than those obtained for nonobligate complexes by most extant interface prediction methods. We find furthermore that a sizable fraction (24%) of the interfaces in models ranked as incorrect in the CAPRI assessment are actually correctly predicted (recall and precision ≥50%), and that these models contribute to 70% of the correct docking-based interface predictions overall. Our analysis proves that docking methods are much more successful in identifying interfaces than in predicting complexes, and suggests that these methods have an excellent potential of addressing the interface prediction challenge. © 2010 Wiley-Liss, Inc.

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