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At least 109 records · Page 6Linked to original sources
PubMed2005

Mechanical resistance of proteins explained using simple molecular models.

Recent experiments have demonstrated that proteins unfold when two atoms are mechanically pulled apart, and that this process is different to when heated or when a chemical denaturant is added to the solution. Experiments have also shown that the response of proteins to external forces is very diverse, some of them being "hard," and others "soft." Mechanical resistance originates from the presence of barriers on the energy landscape; together, experiment and simulation have demonstrated that unfolding occurs through alternative pathways when different pairs of atoms undergo mechanical extension. Here we use simulation to probe the mechanical resistance of six structurally diverse proteins when pulled in different directions. For this, we use two very different models: a detailed, transferable one, and a coarse-grained, structure-based one. The coarse-grained model gives results that are surprisingly similar to the detailed one and qualitatively agree with experiment; i.e., the mechanical resistance of different proteins or of a single protein pulled in different directions can be predicted by simulation. The results demonstrate the importance of pulling direction relative to the local topology in determining mechanical stability, and rationalize the effect of the location of importation/degradation tags on the rates of mitochondrial import or protein degradation in vivo.

Biophysics↗
PubMed1999

Receptor-ligand interaction and molecular modelling.

A number of computational methods for the description of the ligand-receptor interaction that were developed in the past decade are reviewed in this paper. The central two sections introduce the methods that are already established as useful tools for the qualitative and quantitative description of ligand-receptor complexes, either when the detailed atomic structure of the receptor is known or not. The following section gives two examples of the application of the described methodology on two limiting cases.

Drug Design↗
PubMed2005

MESHI: a new library of Java classes for molecular modeling.

UNLABELLED: Adapting a modular and object-oriented approach in the design of molecular modeling packages may reduce the software development barrier between ideas and their programed applications. Towards this goal we developed MESHI, a new, strictly object-oriented, molecular modeling suite written in Java. MESHI provides a comprehensive library of extendable classes for all the essential components of molecular modeling: molecular and geometry elements, energy functions and optimization methods. AVAILABILITY: MESHI and its related documentation are freely available at http://www.cs.bgu.ac.il/~meshi; the MESHI API is available at http://www.cs.bgu.ac.il/~meshi/API CONTACT: keasar@cs.bgu.ac.il SUPPLEMENTARY INFORMATION: The Supplementary information includes (1) a detailed description of several key packages and classes, and (2) a brief presentation of results achieved by using the MESHI application--Beautify--in the CASP6 experiment.

Computer Simulation↗
PubMed2002

Development of quantitative structure-property relationship models for pseudoternary microemulsions formulated with nonionic surfactants and cosurfactants: application of data mining and molecular modeling.

Data mining, computer-aided molecular modeling, descriptor calculation and multiple linear regression techniques were utilized to produce statistically significant and predictive models for O/W and W/O microemulsions. The literature was scanned over the last 20 years, subsequently, 68 phase diagrams from eight different references were collected. Molecular modeling techniques were then applied on the components of the microemulsion systems to generate plausible 3-D structures. Subsequently, various physicochemical descriptors were calculated based on the resulting 3-D structures. The generated descriptors were correlated with microemulsion existence areas utilizing multiple linear regression analysis (MLR). The generated models were statistically cross-validated and were found to be of significant predictive power. Furthermore, the resulting models allowed better understanding of the process of microemulsion formation.

Drug Compounding↗
PubMed1998

A simple molecular model of neurulation.

A molecular model for the morphogenesis of the central nervous system is built and solved by computer. The formalism rests on molecular-biological data gathered from insects and vertebrates during neural differentiation and neuronal fate specification. Two genetic, hierarchically organized switches are introduced, one associated with f1p4al tissue formation, and the other with neuronal specification. The model switches evolve in time, setting up very similar "prepatterns" of genetic activity in both insects and vertebrates, as observed experimentally. We introduce the hypothesis that cell adhesion and motion are regulated by the switches. If cell motion is turned on by the neural switch, the whole neural tissue (neural plate) thickens, buckles, and folds, ultimately creating a closed neural tube (primary neurulation). When mitoses are more frequent in neural plate tissue, ingression of a neural cell mass takes place instead (secondary neurulation). If cell motions are controlled by the neuronal switch, rather than by the neural one, the differentiation of isolated neuroblasts is observed, which delaminate individually (as in insect neural cord formation). The model thus displays the three major known patterns of neurogenesis; the transition between the vertebrate and insect cases is predicted to result from changes in genetic regulation downstream of the switch genes, and affecting cell adhesion and motility properties. Little is known experimentally about the concerned pathways: their importance as a fruitful area for future investigation is emphasized by our theoretical results.

Animals↗
PubMed2005

Trimer based polarization as a multibody molecular model. Application to hydrogen fluoride.

A molecular modeling approach is introduced as a way to treat multibody (more than two molecules) contributions to the intermolecular potential. There are two key features to the method. First, it employs polarizable electrostatics on the molecules, but converges the charges and fields for only three molecules at a time, taken separately for all trimers (three molecules falling within a cutoff distance) in the system. This feature introduces significant computational savings when applied in Monte Carlo simulation (in comparison to a full N-body polarization treatment), as movement of a single molecule does not require re-converging of the polarization of all molecules, and it achieves this without approximations that cause the value of the energy to depend on the history of the simulation. Second, the approach defines the polarization energy in excess of the pairwise contribution, meaning that the trimer energy has subtracted from it the sum of the energies obtained by converging the polarization of each molecule pair in the trimer. This feature is advantageous because it removes the need (often found in polarizable models) to stiffen inappropriately the repulsive part of the pair potential. The polarization contribution is thus a purely three-body potential. The approach is applied to model hydrogen fluoride, which in experiments exhibits unusual properties that have proven difficult to capture well by molecular models. The new HF model is shown to be much more successful than previous modeling efforts in obtaining agreement with a broad range of experimental data (volumetric properties, heat effects, molecular structure, and vapor-liquid equilibria).

Journal Article↗
PubMed2003

Molecular modelling of entanglement.

The modelling of molecular entanglement in polymeric materials is an old problem, and has evolved gradually over the last 60 years, with two key approaches: the network model of Green & Tobolsky, and the tube model of Edwards and de Gennes. We will show that these models can be merged together in a straightforward manner. The resulting model, called the dual slip-link model, can be handled by computer simulation, and it can predict the linear and nonlinear rheological behaviours of linear and star polymers with arbitrary molecular weight distribution.

Models, Molecular↗
PubMed1994

Molecular modeling studies of aldose reductase inhibitors.

Molecular modeling studies using the AM1 quantum chemical method and a torsional fitting method have been conducted on a series of aldose reductase inhibitors (ARIs) possessing an ionizable group and/or functional group susceptible to nucleophilic attack with the aim of defining the spatial position of ARI pharmacophores. AM1 quantum chemical calculations were conducted on ARIs possessing only an ionizable group to obtain their optimized geometries. These optimized structures were then superimposed on the model compound spirofluorene-9,5'-imidazolidine-2',4'-dione (17). This superposition study suggests that a negative charge center residing in the vicinity of the 2'-oxygen of the imidazolidine-2',4'-dione ring participates in the binding interactions. In addition, the optimized geometries of ARIs possessing both an ionizable group and an electronegative functional group were superimposed on spirofluorene-9,5'-imidazolidine-2',4'-dione (17). The latter results also suggest the presence of a region where nucleophilic substitution can occur.

Aldehyde Reductase↗
PubMed1998

Dentin phosphoprotein sequence motifs and molecular modeling: conformational adaptations to mineral crystals.

Molecular modeling has been used to investigate structural features of oligopeptides derived from possible primary structure motifs in highly phosphorylated dentin phosphoprotein (PP-H), the predominant noncollagenous protein in dentin. It contains a large number of aspartate (Asp) and phosphoserine (Pse) residues, the latter proposedly crucial for the PP-H function as a mineral nucleator. In this work, computer fitting and subsequent structural adaptation of model peptides, built exclusively from Asp and Pse, to the known crystal structures of hydroxyapatite (HAP) and octacalcium phosphate (OCP) were performed. The results show that, when considering conformational energies of fitted single strand oligo-peptides, either crystal will serve. Within a narrow range, fitting to OCP was slightly favored, except for oligo(Pse-Pse-Asp-Asp), which showed a slightly better fit to HAP. Energy differences between crystal-adapted and non-adapted freely minimized peptides showed that oligo(Pse-Asp) docked to either HAP or OCP were the energetically most favored adaptations. Fitting of minimized triple anti-parallel beta-strands of oligo(Pse-Asp) or oligo(Pse-Pse-Asp), motifs found in published sequences of rat, mouse, and bovine PP-H, revealed that a (001) crystal face of HAP, but most likely not OCP, may be formed by these beta-sheet models. The former motif is more advantageous in this respect.

Amino Acid Sequence↗
PubMed1984

Molecular model for messenger RNA splicing.

A molecular model is presented for a messenger RNA (mRNA) "splice region." The model requires cation coordination to reduce backbone-backbone electrostatic repulsion and it allows for every base residue on the pre-mRNA to be stacked in A-form helical geometry with a recognition element on the intron or exon (or both) sides of the splice junction. The two nucleotides involved in the initial steps of the cleavage-ligation mechanism must adopt a non-A-form geometry, which ideally positions reactive groups on the pre-mRNA for the necessary catalytic chemistry. The model is also consistent with available biochemical data on splicing reactions.

Adenosine Triphosphate↗
PubMed1999

Molecular modelling of the 5-hydroxytryptamine receptors.

Molecular models of the 5-hydroxytryptamine receptors are reviewed with particular emphasis upon ligand receptor interactions. The use of such models in the areas of drug design and the design and rationalisation of experiments is discussed. It is clear that many groups have modelled the 5-HT receptors using either the bacteriorhodopsin structure, rhodopsin electron density map or rhodopsin alpha-carbon template. Although it is difficult to assess the accuracy of these models it is expected that the rhodopsin based models show improved accuracy over the bacteriorhodopsin based models. Nevertheless models that are thoroughly validated with experimental mutagenesis and ligand binding data are useful in a qualitative sense providing ideas upon target compounds to synthesise and the design and rationalisation of mutagenesis experiments.

Amino Acid Sequence↗
PubMed2002

Molecular modeling in cysteine protease inhibitor design.

The application of various molecular modeling techniques has been recently reported in the design of several new cysteine protease inhibitors. Computational chemistry techniques have been used to understand and predict enzyme-inhibitor interactions and also to study enzyme mechanism and inhibitor reactivity. This review focuses on examples that use structure-based design or reflect cysteine proteases as a target class. In several cases X-ray crystallography and molecular modeling have significantly facilitated the inhibitor design process. Cysteine proteases can present extra challenges in molecular modeling, due to the covalent binding modes and the reactive nature of many of the inhibitors. We also discuss some of the key challenges in developing new tools to evaluate these properties and help in making informed decisions about new templates and leads.

Animals↗
PubMed1997

Molecular modeling and 3D-QSAR studies on the interaction mechanism of tripeptidyl thrombin inhibitors with human alpha-thrombin.

The mechanism of inhibition of peptidyl inhibitors with thrombin was studied using molecular modeling, molecular mechanics, and CoMFA statistical analysis. A new procedure for the elucidation of binding conformations, BCSPL, is described and was employed to obtain the binding conformers of a series of 18 tripeptidyl thrombin inhibitors. Energetic studies and QSAR analysis of the BCSPL-derived conformers indicated a modest correlation between the calculated binding energies of the title compounds and their inhibitory activities to human alpha-thrombin. CoMFA analysis of the BCSPL alignment resulted in a satisfactory model of the thrombin active site.

Antithrombins↗