Genetic diversity in the IZUMO1-JUNO protein-receptor pair involved in human reproduction.

Fertilization in mammals begins with the union of egg and sperm, an event that starts a cascade of cellular processes. The molecular-level understanding of these processes can guide the development of new strategies for controlling and/or promoting fertilization, and inform researchers and medical professional on the best choice of interventions. The proteins encoded by the IZUMO1 and JUNO genes form a ligand-receptor protein pair involved in the recognition of sperm and egg.

Functional variants of human papillomavirus type 16 demonstrate host genome integration and transcriptional alterations corresponding to their unique cancer epidemiology.

Background: Human papillomaviruses (HPVs) are a worldwide burden as they are a widespread group of tumour viruses in humans. Having a tropism for mucosal tissues, high-risk HPVs are detected in nearly all cervical cancers. HPV16 is the most common high-risk type but not all women infected with high-risk HPV develop a malignant tumour.

Molecular Dynamics of Fibrinogen Adsorption onto Graphene, but Not onto Poly(ethylene glycol) Surface, Increases Exposure of Recognition Sites That Trigger Immune Response.

Changes in the conformation of blood proteins due to their binding to nonbiological surfaces is the initial step in the chain of immunological reactions to foreign bodies. Despite the large number of experimental studies that have been performed on fibrinogen adsorption to nonbiological surfaces, a clear picture describing this complex process has eluded researchers to date. Developing a better understanding of the behavior of bioactive fibrinogen motifs upon their interaction with surfaces may facilitate the design of advanced materials with improved biocompatibility.

Systematic discovery of molecular probes targeting multiple non-orthosteric and spatially distinct sites in the botulinum neurotoxin subtype A (BoNT/A).

The development of molecular probes targeting proteins has traditionally relied on labeling compounds already known to bind to the protein of interest. These known ligands bind to orthosteric or allosteric sites in their target protein as a way to control their activity. Binding pockets other than known orthosteric or allosteric sites may exist that are large enough to accommodate a ligand without significantly disrupting protein activity.

N-(2,4)-dinitrophenyl-L-arginine Interacts with EphB4 and Functions as an EphB4 Kinase Modulator.

The erythropoietin-producing hepatocellular carcinoma receptor B4 is a receptor tyrosine kinase whose expression is preserved in various malignancies, including colon, gastric, and breast carcinoma. Hepatocellular carcinoma receptor B4 presence in tumor cells and involvement in cancer suppression makes it a potential therapeutic target for activating compounds. Moreover, modulators of its activity also have a strong potential to be used in diagnosis and therapy monitoring.

Identifying potential selective fluorescent probes for cancer-associated protein carbonic anhydrase IX using a computational approach.

Carbonic anhydrase IX (CAIX) is a biomarker for tumor hypoxia. Fluorescent inhibitors of CAIX have been used to study hypoxic tumor cell lines. However, these inhibitor-based fluorescent probes may have a therapeutic effect that is not appropriate for monitoring treatment efficacy.

Principal component analysis of binding energies for single-point mutants of hT2R16 bound to an agonist correlate with experimental mutant cell response.

Directed evolution is a technique that enables the identification of mutants of a particular protein that carry a desired property by successive rounds of random mutagenesis, screening, and selection. This technique has many applications, including the development of G protein-coupled receptor-based biosensors and designer drugs for personalized medicine. Although effective, directed evolution is not without challenges and can greatly benefit from the development of computational techniques to predict the functional outcome of single-point amino acid substitutions.

Creating and virtually screening databases of fluorescently-labelled compounds for the discovery of target-specific molecular probes.

Our group has recently demonstrated that virtual screening is a useful technique for the identification of target-specific molecular probes. In this paper, we discuss some of our proof-of-concept results involving two biologically relevant target proteins, and report the development of a computational script to generate large databases of fluorescence-labelled compounds for computer-assisted molecular design. The virtual screening of a small library of 1,153 fluorescently-labelled compounds against two targets, and the experimental testing of selected hits reveal that this approach is efficient at identifying molecular probes, and that the screening of a labelled library is preferred over the screening of base compounds followed by conjugation of confirmed hits.

Binding of solvated peptide (EPLQLKM) with a graphene sheet via simulated coarse-grained approach.

Binding of a solvated peptide A1 ((1)E (2)P (3)L (4)Q (5)L (6)K (7)M) with a graphene sheet is studied by a coarse-grained computer simulation involving input from three independent simulated interaction potentials in hierarchy. A number of local and global physical quantities such as energy, mobility, and binding profiles and radius of gyration of peptides are examined as a function of temperature (T). Quantitative differences (e.

Paclitaxel is an inhibitor and its boron dipyrromethene derivative is a fluorescent recognition agent for botulinum neurotoxin subtype A.

We have successfully identified one new inhibitor and one new fluorescent recognition agent for the botulinum neurotoxin subtype A (BoNT/A) using the virtual screening protocol "protein scanning with virtual ligand screening" (PSVLS). Hit selection used an in-house developed holistic binding scoring method. Selected hits were tested experimentally for inhibitory activity using fluorescence resonance energy transfer (FRET) assays against the light chain (catalytic domain) of BoNT/A.

Genetics of sweet taste preferences.

Sweet taste is a powerful factor influencing food acceptance. There is considerable variation in sweet taste perception and preferences within and among species. Although learning and homeostatic mechanisms contribute to this variation in sweet taste, much of it is genetically determined.

Sweet taste receptor gene variation and aspartame taste in primates and other species.

Aspartame is a sweetener added to foods and beverages as a low-calorie sugar replacement. Unlike sugars, which are apparently perceived as sweet and desirable by a range of mammals, the ability to taste aspartame varies, with humans, apes, and Old World monkeys perceiving aspartame as sweet but not other primate species. To investigate whether the ability to perceive the sweetness of aspartame correlates with variations in the DNA sequence of the genes encoding sweet taste receptor proteins, T1R2 and T1R3, we sequenced these genes in 9 aspartame taster and nontaster primate species.

A cluster-aware graphical user interface for a virtual ligand screening tool.

In this paper, we describe the design and implementation of a Graphical User Interface (GUI) for Cassandra, a computer application for Virtual Ligand Screening (VLS). The GUI was designed using Trolltech QT4 and Perl, and serves the purpose of making the execution of Cassandra more user-friendly. Through this GUI, users can manage multiple concurrent, interactive data paths both on a single machine and on a High Performance Computing Cluster (HPCC).

A portable bioinformatics course for upper-division undergraduate curriculum in sciences.

This article discusses the challenges that bioinformatics education is facing and describes a bioinformatics course that is successfully taught at the California State Polytechnic University, Pomona, to the fourth year undergraduate students in biological sciences, chemistry, and computer science. Information on lecture and computer practice topics, free for academic use software and web links required for the laboratory exercises and student surveys for two instances of the course, is presented. This course emphasizes hands-on experience and focuses on developing practical skills while providing a solid knowledge base for critically applying these skills.

A molecular dynamics study of the correlations between solvent-accessible surface, molecular volume, and folding state.

We analyzed the correlations between molecular volume, solvent-accessible surface, and folding state (secondary structure content) for unfolded conformers of alpha (holo- and apomyoglobin) and beta (retinal-binding protein) proteins and a small water-soluble alanine-rich alpha-helical peptide. Conformers with different degrees of folding were obtained using molecular dynamics at constant temperature and pressure with implicit solvent (dielectric constant adjustment) for all four systems and with explicit solvent for the single helix peptide. Our results support the view that unfolded conformations are not necessary extended, that volume variation is not a good indication of folding state and that the simple model of water penetrating the interior of the protein does not explain the increase in volume upon unfolding.

Predictions of CCR1 chemokine receptor structure and BX 471 antagonist binding followed by experimental validation.

A major challenge in the application of structure-based drug design methods to proteins belonging to the superfamily of G protein-coupled receptors (GPCRs) is the paucity of structural information (1). The 19 chemokine receptors, belonging to the Class A family of GPCRs, are important drug targets not only for autoimmune diseases like multiple sclerosis but also for the blockade of human immunodeficiency virus type 1 entry (2). Using the MembStruk computational method (3), we predicted the three-dimensional structure of the human CCR1 receptor.

Modeling the human PTC bitter-taste receptor interactions with bitter tastants.

We employed the first principles computational method MembStruk and homology modeling techniques to predict the 3D structures of the human phenylthiocarbamide (PTC) taste receptor. This protein is a seven-transmembrane-domain G protein-coupled receptor that exists in two main forms worldwide, designated taster and nontaster, which differ from each other at three amino-acid positions. 3D models were generated with and without structural similarity comparison to bovine rhodopsin.

Test of the Binding Threshold Hypothesis for olfactory receptors: explanation of the differential binding of ketones to the mouse and human orthologs of olfactory receptor 912-93.

We tested the Binding Threshold Hypothesis (BTH) for activation of olfactory receptors (ORs): To activate an OR, the odorant must bind to the OR with binding energy above some threshold value. The olfactory receptor (OR) 912-93 is known experimentally to be activated by ketones in mouse, but is inactive to ketones in human, despite an amino acid sequence identity of approximately 66%. To investigate the origins of this difference, we used the MembStruk first-principles method to predict the tertiary structure of the mouse OR 912-93 (mOR912-93), and the HierDock first-principles method to predict the binding site for ketones to this receptor.

The MPSim-Dock hierarchical docking algorithm: application to the eight trypsin inhibitor cocrystals.

To help improve the accuracy of protein-ligand docking as a useful tool for drug discovery, we developed MPSim-Dock, which ensures a comprehensive sampling of diverse families of ligand conformations in the binding region followed by an enrichment of the good energy scoring families so that the energy scores of the sampled conformations can be reliably used to select the best conformation of the ligand. This combines elements of DOCK4.0 with molecular dynamics (MD) methods available in the software, MPSim.

Predicted 3-D structures for mouse I7 and rat I7 olfactory receptors and comparison of predicted odor recognition profiles with experiment.

The first step in the perception of an odor is the activation of one or more olfactory receptors (ORs) following binding of the odorant molecule to the OR. In order to initiate the process of determining how the molecular level receptor-odorant interactions are related to odor perception, we used the MembStruk computational method to predict the three-dimensional (3-D) structure of the I7 OR for both mouse and rat. We then used the HierDock ligand docking computational method to predict the binding site and binding energy for the library of 56 odorants to these receptors for which experiment response data are now available.

Making sense of olfaction through predictions of the 3-D structure and function of olfactory receptors.

We used the MembStruk first principles computational technique to predict the three-dimensional (3-D) structure of six mouse olfactory receptors (S6, S18, S19, S25, S46 and S50) for which experimental odorant recognition profiles are available for a set of 24 odorants (4-9 carbons aliphatic alcohols, acids, bromo-acids and diacids). We used the HierDock method to scan each predicted OR structure for potential odorant binding site(s) and to calculate binding energies of each odorant in these binding sites. The calculated binding affinity profiles are in good agreement with experimental activation profiles, validating the predicted 3-D structures and the predicted binding sites.

First principles predictions of the structure and function of g-protein-coupled receptors: validation for bovine rhodopsin.

G-protein-coupled receptors (GPCRs) are involved in cell communication processes and with mediating such senses as vision, smell, taste, and pain. They constitute a prominent superfamily of drug targets, but an atomic-level structure is available for only one GPCR, bovine rhodopsin, making it difficult to use structure-based methods to design receptor-specific drugs. We have developed the MembStruk first principles computational method for predicting the three-dimensional structure of GPCRs.

The predicted 3D structure of the human D2 dopamine receptor and the binding site and binding affinities for agonists and antagonists.

Dopamine neurotransmitter and its receptors play a critical role in the cell signaling process responsible for information transfer in neurons functioning in the nervous system. Development of improved therapeutics for such disorders as Parkinson's disease and schizophrenia would be significantly enhanced with the availability of the 3D structure for the dopamine receptors and of the binding site for dopamine and other agonists and antagonists. We report here the 3D structure of the long isoform of the human D2 dopamine receptor, predicted from primary sequence using first-principles theoretical and computational techniques (i.

Predicted 3D structure for the human beta 2 adrenergic receptor and its binding site for agonists and antagonists.

We report the 3D structure of human beta2 adrenergic receptor (AR) predicted by using the MembStruk first principles method. To validate this structure, we use the HierDock first principles method to predict the ligand-binding sites for epinephrine and norepinephrine and for eight other ligands, including agonists and antagonists to beta 2 AR and ligands not observed to bind to beta 2 AR. The binding sites agree well with available mutagenesis data, and the calculated relative binding energies correlate reasonably with measured binding affinities.