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Techniques for visualization of carbohydrate molecules.

Standard molecular visualizations, such as the classic ball-and-stick model, are not suitable for large, complex molecules because the overall molecular structure is obscured by the atomic detail. For proteins, the more abstract ribbon and cartoon representations are instead used to reveal large scale molecular conformation and connectivity. However, there is currently no accepted convention for simplifying oligo- and polysaccharide structures. We introduce two novel visualization algorithms for carbohydrates, incorporated into a visualization package, CarboHydra. Both algorithms highlight the sugar rings and backbone conformation of the carbohydrate chain, ignoring ring substituents. The first algorithm, termed PaperChain, emphasizes the type and conformation of the carbohydrate rings. The second, Twister, emphasizes the relative orientation of the rings. We further include two rendering enhancements to augment these visualizations: silhouettes edges and a translucent overlay of the ball-and-stick atomic representation. To demonstrate their utility, the algorithms and visualization enhancements are here applied to a variety of carbohydrate molecules. User evaluations indicate that they present a more useful view of carbohydrate structure than the standard ball-and-stick representation. The algorithms were found to be complementary, with PaperChain particularly effective for smaller carbohydrates and Twister useful at larger scales for highlighting the backbone twist of polysaccharides.

Algorithms↗

Analysis of the domain interactions between the protease and helicase of NS3 in dengue and hepatitis C virus.

Flaviviridae non-structural 3 protein (NS3) is a multifunctional enzyme, composed by a protease domain (NS3pro) and an RNA helicase domain (NS3hel). The activities present in NS3 have proved to be critical for viral replication. The replicative cycle of Flaviviridae requires coordinated regulation of all the activities present in the full-length NS3 protein, however, the exact nature of these interactions remains unclear. The present work aimed to determine common structural features between NS3 of dengue and hepatitis C viruses and to characterize residues involved in the regulation of the interdomain motions between NS3pro and NS3hel. Analysis of the root mean square (RMS) variation shows that NS3pro increases the stability of subdomain 1 of the RNA helicase. Moreover, the dynamic behaviour of the carboxy terminus of NS3hel, supports the hypothesis that, upon release of the carboxy-terminus from NS3pro, the residues involved in this interaction are folded back into the last alpha-helix. Using normal mode analysis, we characterized slow collective motions of NS3, and observed that the two lowest-frequency normal modes are enough to describe reorientations of NS3pro relative to NS3hel. These movements induced an increment in the exposure of the active site of NS3pro that can be important during the proteolytic processing of the viral polyprotein. The third low-frequency normal mode was correlated to subdomain reorientations of NS3hel, similar to those proposed during NTP hydrolysis and dsRNA unwinding. Based on these data, we support a dynamic model, in which the domain movements between NS3pro and NS3hel result in the regulation of its activities.

Binding Sites↗

Comparison of homology models and X-ray structures of the nuclear receptor CAR: assessing the structural basis of constitutive activity.

The constitutive androstane receptor (CAR) possesses an intrinsic basal activity whose structural basis has been analysed during the last decade. Recently, we published a homology model of the CAR ligand binding domain (LBD) based on the X-ray structures of the closely related pregnane X (PXR) and vitamin D (VDR) receptor. A detailed analysis of the homology model and molecular dynamics (MD) simulations afforded us to propose a potential mechanism underlying the constitutive activity of CAR. Almost simultaneously, X-ray structures of human and mouse CAR LBD were released. In the present study, a detailed analysis and comparison of homology model and X-ray structures is carried out in order to evaluate the quality and reliability of our homology modelling procedure. The hypothesis of the constitutive activity which we proposed on the basis of our modelling results was tested for consistency with the crystal structures. In addition, the features stated to be essential for the basal activity based on the X-ray data were investigated by means of molecular dynamics simulations. Our results show that the homology modelling procedure was able to predict the CAR LBD structure with high accuracy. Structural features that have been revealed as critical for constitutive activity in the model are also observed in the X-ray structures. Furthermore, the MD simulations of the CAR X-ray structures and a detailed analysis of other NRs clarify the role of distinct structural features that have been assigned an important role for the constitutive activity.

Amino Acid Sequence↗

Molecular modeling benzo[a]pyrene N2-dG adducts in the two overlapping active sites of the Y-family DNA polymerase Dpo4.

The potent, ubiquitous environmental mutagen/carcinogen benzo[a]pyrene (B[a]P) induces a single major adduct [+ta]-B[a]P-N2-dG, whose bypass in most cases results in either no mutation (dCTP insertion) or a G-->T mutation (dATP insertion). Translesion synthesis (TLS) of [+ta]-B[a]P-N2-dG generally requires DNA polymerases (DNAPs) in the Y-family, which exist in cells to bypass DNA damage caused by chemicals and radiation. A molecular dynamics (MD) study is described with dCTP opposite [+ta]-B[a]P-N2-dG in Dpo4, which is the best studied Y-family DNAP from a structural point of view. Two orientations of B[a]P-N2-dG (BPmi5 and BPmi3) are considered, along with two orientations of the dCTP (AS1 and AS2), as outlined next. Based on NMR studies, the pyrene moiety of B[a]P-N2-dG is in the minor groove, when paired with dC, and can point toward either the base on the 5'-side (BPmi5) or the 3'-side (BPmi3). Based on published X-ray structures, Dpo4 appears to have two partially overlapping active sites. The architecture of active site 1 (AS1) is similar to all other families of DNAPs (e.g., the shape of the dNTP). Active site 2 (AS2), however, is non-canonical (e.g., the beta- and gamma-phosphates in AS2 are approximately where the alpha- and beta-phosphates are in AS1). In the Dpo4 models generated herein, using the BPmi3 orientation the pyrene moiety of [+ta]-B[a]P-N2-dG points toward the duplex region of the DNA, and is accommodated without distortions in AS1, but with distortions in AS2. Considering the BPmi5 orientation, the pyrene moiety points toward the ss-region of DNA in Dpo4, and sits in a hole defined by the fingers and little fingers domain ("chimney"); BPmi5 is accommodated in AS2 without significant distortions, but poorly in AS1. In summary, when dCTP is paired with [+ta]-B[a]P-N2-dG in the two overlapping active sites in Dpo4, the pyrene in the BPmi3 orientation is accommodated better in active site 1 (AS1), while the pyrene in the BPmi5 orientation is accommodated better in AS2. Finally, we discuss why Y-family DNAPs might have two catalytic active sites.

Benzopyrenes↗

Quantitative structure-activity relationship studies for the prediction of antifungal activity of N-arylbenzenesulfonamides against Botrytis cinerea.

The Botrytis cinerea is one of the most interesting fungal pathogens. It can infect almost every plant and plant part and cause early latent infections which damage the fruit before ripening. The QSAR is an alternative method for the research of new and better fungicides against B. cinerea. This paper describes the results of applying a topological sub-structural molecular design (TOPS-MODE) approach for predicting the antifungal activity of 28 N-arylbenzenesulfonamides. The model described 86.1% of the experimental variance, with a standard deviation of 0.223. Leave-one-out and leave-group-out cross validation was carried out with the aim of evaluating the predictive power of the model. The values of their respective squared correlations coefficients were 0.754 and 0.741. The TOPS-MODE approach was compared with three other predictive models, but none of these could explain more than 72.8% of the variance with the same number of variables. In addition, this approach enabled the assessment of the contribution of different bonds to antifungal activity, thereby making the relationships between structure and biological activity more transparent. It was found that the fungicidal activity of the chemicals analyzed was increased by the presence of a sulfonamide group bonded to two aromatics rings, making this group the most important of the molecule. The majority of the substituents present in the aromatic rings have an electron withdrawing effect and they contribute to a smaller degree than the sulfonamide group to the property under study. The aromatic moiety plays an important role in this activity; its contribution changes with different substituents. Generally, the nitro group has a positive and great contribution to the biological property but when this group is involved in some compounds in ortho effect with the SO2 moiety of the sulfonamide group a lower value of contribution is observed for both groups.

Botrytis↗

Molecular modelling of the GABAA ion channel protein.

The GABAA ion channel protein is central to the mechanism of action of general anaesthetics and thus to the phenomenon of human consciousness. A molecular model of the alpha1beta2gamma2 gamma-aminobutyric acid type-A (GABAA) ligand-gated ion channel protein has been constructed. The cryo-electron microscopy structure of the nicotinic acetylcholine receptor (nAChR) from Torpedo marmorata and the X-ray crystal structure of the acetylcholine binding protein (AChBP) from Lymnaea stagnalis were used as starting templates for comparative modelling. Features of the modelling approach used in the development of this GABAA model include: (1) multiple sequence alignment of members of the Cys-loop superfamily; (2) the design and implementation of a quasi-ab initio loop modelling algorithm; (3) expansion of the transmembrane domain (TMD) ion pore to model the open-state of the GABAA channel; (4) hydrophobicity analysis of the TMD to refine the structure in regions involved in general anaesthetic binding. The final model of the alpha1beta2gamma2 GABAA protein agrees with available experimental data concerning general anaesthetics.

Amino Acid Sequence↗

Classification of alpha-cyclodextrins inclusion complexes into Type 1 and Type 2: a prelude to log K prediction.

Molecular Interaction Fields (MIFs) were used in combination with a small number of geometrical descriptors to separate nine alpha-CD complexes into Type 1 and Type 2, two classes, respectively, containing complexes having high log K and low log K values (stoichiometry of 1:1). Calculations were performed on the crystallographic conformations of alpha-CDs after their separation from the ligand and without minimization. The results show that the computational strategy adopted is able to distinguish Type 1 from Type 2 complexes and that it can be applied to all CD families.

Carbohydrate Conformation↗

Computer aided comparative analysis of the binding modes of the adenosine receptor agonists for all known subtypes of adenosine receptors.

Molecular models of all known subtypes (A1, A2A, A2B, and A3) of the human adenosine receptors were built in homology with bovine rhodopsin. These models include the transmembrane domain as well as all extracellular and intracellular hydrophilic loops and terminal domains. The molecular docking of adenosine and 46 selected derivatives was performed for each receptor subtype. A binding mode common for all studied agonists was proposed, and possible explanations for differences in the ligand activities were suggested.

Adenosine↗

Modelling and study of cyclosporin A and related compounds in complexes with a Trypanosoma cruzi cyclophilin.

Cyclophilins (CyPs) are enzymes involved in protein folding, catalyzing the isomerisation of peptidyl prolyl bonds in proteins and peptides between the cis- and trans-conformations. They are also the major cellular target for the immunosuppressive drug Cyclosporin A (CsA). In Trypanosoma cruzi, the most abundantly expressed CyP is an isoform of 19 kDa, TcCyP19, in which the enzymatic activity is inhibited by CsA. Among a reported set of CsA analogues, two non-immunosuppressive compounds, H-7-94 and F-7-62, proved to be the best inhibitors of TcCyP19 enzymatic activity as well as the most efficient trypanocidal drugs. With the objective of analysing, at the molecular level, how the structural differences between the three above-mentioned inhibitors justify their different inhibitory activity on TcCyP19, three-dimensional molecular modelling structures were generated to computationally simulate behaviours and interactions. An energy-minimized model of each binary complex in water with ions was obtained. These models were then used as starting point for molecular dynamic simulations, performed with GROMOS96 program. With the resulting set of co-ordinates and energies, a comparison of the interaction between CsA and both CsA analogues in T. cruzi and human cyclophilins were performed. Within the different magnitudes analysed, the total potential complex energy exhibited the best correlation with the experimental data. The results obtained in this study support the use of this methodology when designing new lead inhibitor compounds.

Amino Acid Sequence↗

A simple method to study cellular migration.

We describe here a simple and fast method for the characterisation of cell motion. By projecting on a single plane different positions of the cell a ribbon is generated, whose characteristics can be related to the type of motion. The proposed method allows both to determine, very quickly, the motility of a population of cells and to investigate and characterise properties of a single cell's motion. The methodology presented here can be applied to a large range of cell movement and also adapted and extended to other problems involving biological motion.

Animals↗

Quantitative analysis of accuracy of an inertial/acoustic 6DOF tracking system in motion.

An increasing number of neuroscience experiments are using virtual reality to provide a more immersive and less artificial experimental environment. This is particularly useful to navigation and three-dimensional scene perception experiments. Such experiments require accurate real-time tracking of the observer's head in order to render the virtual scene. Here, we present data on the accuracy of a commonly used six degrees of freedom tracker (Intersense IS900) when it is moved in ways typical of virtual reality applications. We compared the reported location of the tracker with its location computed by an optical tracking method. When the tracker was stationary, the root mean square error in spatial accuracy was 0.64 mm. However, we found that errors increased over ten-fold (up to 17 mm) when the tracker moved at speeds common in virtual reality applications. We demonstrate that the errors we report here are predominantly due to inaccuracies of the IS900 system rather than the optical tracking against which it was compared.

Acceleration↗

Modelling of interaction between a spatula and a human brain.

This paper describes a method for surgery simulation, or more specifically a learning system of how to use a brain spatula. Improper use of brain spatulas can lead to brain tissue lesions such as tearing of brain tissue and ischemia. The idea is to provide surgeons with a tool which can teach them the correlation between deformation and applied force. The system includes a Finite Element based model of the brain in a Virtual Reality setup with haptic feedback. The physical model links the shape of the deformable model with the associated force. The interaction between the spatula and the brain model is handled by a collision response method which aims at smoothing the discrete haptic feedback. The experimental results are promising even though the used force feedback device is somewhat constraining the realism.

Algorithms↗

Modelling liver tissue properties using a non-linear visco-elastic model for surgery simulation.

In this work, we introduce an extension of the linear elastic tensor-mass method allowing fast computation of non-linear and visco-elastic mechanical forces and deformations for the simulation of biological soft tissue. We aim at developing a simulation tool for the planning of cryogenic surgical treatment of liver cancer. Percutaneous surgery simulation requires accurate modelling of the mechanical behaviour of soft tissue, and previous experimental characterizations have shown that linear elasticity is only a coarse approximation of the real properties of biological tissues. We first show that our model can simulate different types of non-linear and visco-elastic mechanical behaviours at speeds which are compatible with real-time applications. Then an experimental setup is presented which was used to characterize the mechanical properties of deer liver tissue under perforation by a biopsy needle. Experimental results demonstrate that a linear model is not suitable for simulating this application, while the proposed model succeeds in accurately modelling the axial load measured on the needle.

Animals↗

Removing tetrahedra from manifold tetrahedralisation: application to real-time surgical simulation.

This paper proposes an efficient method for removing tetrahedra from a tetrahedral mesh while keeping its manifold property. We first define precisely the notion of manifold tetrahedral mesh and stress its relevance in the context of real-time surgery simulation. We then provide a method for removing a tetrahedron that complies with the manifold definition. This removal may require in some cases the removal of neighboring tetrahedra. After providing an exhaustive description of the tetrahedron removal algorithm, its efficiency is evaluated for different mesh configurations. This algorithm is currently used in the context of real-time surgery simulation where the action of an ultrasonic lancet can be simulated by the removal of small set of tetrahedra from a tetrahedralisation.

Algorithms↗

A layered model of a virtual human intestine for surgery simulation.

In this paper, we propose a new approach to simulate the small intestine in a context of laparoscopic surgery. The ultimate aim of this work is to simulate the training of a basic surgical gesture in real-time: moving aside the intestine to reach hidden areas of the abdomen. The main problem posed by this kind of simulation is animating the intestine. The problem comes from the nature of the intestine: a very long tube which is not isotropically elastic, and is contained in a volume that is small when compared to the intestine's length. It coils extensively and collides with itself in many places. To do this, we use a layered model to animate the intestine. The intestine's axis is animated as a linear mechanical component. A specific sphere-based model handles contacts and self-collisions. A skinning model is used to create the intestine's volume around the axis. This paper discusses and compares three different representations for skinning the intestine: a parametric surface model and two implicit surface models. The first implicit surface model uses point skeletons while the second uses local convolution surfaces. Using these models, we obtained good-looking results in real-time. Some videos of this work can be found in the online version at doi: 10.1016/j.media.2004.11.006 and at www-imagis.imag.fr/Publications/2004/FLAMCFC04.

Algorithms↗

Generation of variable anatomical models for surgical training simulators.

The generation of variable surgical scenes is a key element for effective training with surgery simulators. Our current research aims at a high fidelity hysteroscopy simulator which challenges the trainee with a new surgical scene in every training session. We previously reported on methods able to generate a broad range of pathologies within an existing healthy organ model. This paper presents the methods necessary to produce variable models of the healthy organ. In order to build a database of uteri, a volunteer study was conducted. The segmentation was carried out interactively, also covering the establishment of an anatomically meaningful correspondence between the individual organs. The variability of the shape parameters has been characterized by principal component analysis. A new method has been developed and tested, allowing the derivation of realistic new instances based on the stochastic model and complying with non-linear shape constraints which are defined and interactively controlled by medical experts.

Computer Graphics↗

Structural analysis of the epitopes on erbB2 interacted with inhibitory or non-inhibitory monoclonal antibodies.

erbB2 oncogene encodes a growth factor receptor. The overexpression of erbB2 was correlated with more aggressive tumors and a poorer prognosis. Some antibodies directed to this molecule have an antitumor effect in vivo, but some antibodies do not. In an attempt to understand the molecular basis of the anti-erbB2 antibody interaction with erbB2 ectodomain (ECD), we analyzed binding epitopes on erbB2 for inhibitory and non-inhibitory antibodies, Herceptin and HF by computer-guided protein engineering and site-directed mutagenesis. Two different interaction domains were identified by molecular docking, computer graphics and distance geometry method and confirmed through studies on a series of mutants of erbB2 ECD. Non-inhibitory antibody HF only recognized N-terminal portion of erbB2 ECD, but inhibitory antibody Herceptin bound to C-terminal portion of it exclusively. The region interacted with inhibitory antibody Herceptin can be an important target for anticancer therapies.

Antibodies, Monoclonal↗

An incremental regression method for graph structured data.

In this paper, we consider learning problems defined on graph-structured data. We propose an incremental supervised learning algorithm for network-based estimators using diffusion kernels. Diffusion kernel nodes are iteratively added in the training process. For each new node added, the kernel function center and the output connection weight are decided according to an empirical risk driven rule based on an extended chained version of the Nadaraja-Watson estimator. Then the diffusion parameters are determined by a genetic-like optimization technique.

Algorithms↗