On the structure and dynamics of the complex of the nucleosome and the linker histone.

Several different models of the linker histone (LH)-nucleosome complex have been proposed, but none of them has unambiguously revealed the position and binding sites of the LH on the nucleosome. Using Brownian dynamics-based docking together with normal mode analysis of the nucleosome to account for the flexibility of two flanking 10 bp long linker DNAs (L-DNA), we identified binding modes of the H5-LH globular domain (GH5) to the nucleosome. For a wide range of nucleosomal conformations with the L-DNA ends less than 65 Å apart, one dominant binding mode was identified for GH5 and found to be consistent with fluorescence recovery after photobleaching (FRAP) experiments.

Brownian dynamics simulation of protein solutions: structural and dynamical properties.

The study of solutions of biomacromolecules provides an important basis for understanding the behavior of many fundamental cellular processes, such as protein folding, self-assembly, biochemical reactions, and signal transduction. Here, we describe a Brownian dynamics simulation procedure and its validation for the study of the dynamic and structural properties of protein solutions. In the model used, the proteins are treated as atomically detailed rigid bodies moving in a continuum solvent.

Cross-species analysis of the glycolytic pathway by comparison of molecular interaction fields.

The electrostatic potential of an enzyme is a key determinant of its substrate interactions and catalytic turnover. Here we invoke comparative analysis of protein electrostatic potentials, along with sequence and structural analysis, to classify and characterize all the enzymes in an entire pathway across a set of different organisms. The electrostatic potentials of the enzymes from the glycolytic pathway of 11 eukaryotes were analyzed by qPIPSA (quantitative protein interaction property similarity analysis).

On the contributions of diffusion and thermal activation to electron transfer between Phormidium laminosum plastocyanin and cytochrome f: Brownian dynamics simulations with explicit modeling of nonpolar desolvation interactions and electron transfer events.

The factors that determine the extent to which diffusion and thermal activation processes govern electron transfer (ET) between proteins are debated. The process of ET between plastocyanin (PC) and cytochrome f (CytF) from the cyanobacterium Phormidium laminosum was initially thought to be diffusion-controlled but later was found to be under activation control (Schlarb-Ridley, B. G.

webPIPSA: a web server for the comparison of protein interaction properties.

Protein molecular interaction fields are key determinants of protein functionality. PIPSA (Protein Interaction Property Similarity Analysis) is a procedure to compare and analyze protein molecular interaction fields, such as the electrostatic potential. PIPSA may assist in protein functional assignment, classification of proteins, the comparison of binding properties and the estimation of enzyme kinetic parameters.

The acidic, glutamine-rich Mpn474 protein of Mycoplasma pneumoniae is surface exposed and covers the complete cell.

The protein Mpn474 encoded by the mpn474 gene of the human-pathogenic Mycoplasma pneumoniae contains 1033 amino acids and has an isoelectric point of 4.79, which is caused by the large excess of glutamic acid residues (11 %). Although the protein lacks recognizable export signals we showed by immuno-electron microscopy that Mpn474 is surface exposed, covering the cell completely.

Calculating enzyme kinetic parameters from protein structures.

Enzyme kinetic parameters can differ between different species and isoenzymes for the same catalysed reaction. Computational approaches to calculate enzymatic kinetic parameters from the three-dimensional structures of proteins will be reviewed briefly here. Enzyme kinetic parameters may be derived by modelling and simulating the rate-determining process.

qPIPSA: relating enzymatic kinetic parameters and interaction fields.

Background: The simulation of metabolic networks in quantitative systems biology requires the assignment of enzymatic kinetic parameters. Experimentally determined values are often not available and therefore computational methods to estimate these parameters are needed. It is possible to use the three-dimensional structure of an enzyme to perform simulations of a reaction and derive kinetic parameters.

Bridging from molecular simulation to biochemical networks.

How can we make the connection between the three-dimensional structures of individual proteins and understanding how complex biological systems involving many proteins work? The modelling and simulation of protein structures can help to answer this question for systems ranging from multimacromolecular complexes to organelles and cells. On one hand, multiscale modelling and simulation techniques are advancing to permit the spatial and temporal properties of large systems to be simulated using atomic-detail structures. On the other hand, the estimation of kinetic parameters for the mathematical modelling of biochemical pathways using protein structure information provides a basis for iterative manipulation of biochemical pathways guided by protein structure.

Comparison of the binding and reactivity of plant and mammalian peroxidases to indole derivatives by computational docking.

The oxidation of melatonin by the mammalian myeloperoxidase (MPO) provides protection against the damaging effects of reactive oxygen species. Indole derivatives, such as melatonin and serotonin, are also substrates of the plant horseradish peroxidase (HRP), but this enzyme exhibits remarkable differences from MPO in the specificity and reaction rates for these compounds. A structural understanding of the determinants of the reactivity of these enzymes to indole derivatives would greatly aid their exploitation for biosynthetic and drug design applications.

Diffusional encounter of barnase and barstar.

We present an analysis of trajectories from Brownian dynamics simulations of diffusional protein-protein encounter for the well-studied system of barnase and barstar. This analysis reveals details about the optimal association pathways, the regions of the encounter complex, possible differences of the pathways for dissociation and association, the coupling of translational and rotation motion, and the effect of mutations on the trajectories. We found that a small free-energy barrier divides the energetically most favorable region into a region of the encounter complex above the barnase binding interface and a region around a second energy minimum near the RNA binding loop.

ProSAT: functional annotation of protein 3D structures.

ProSAT (for Protein Structure Annotation Tool) is a tool to facilitate interactive visualization of non-structure-based functional annotations in protein 3D structures. It performs automated mapping of the functional annotations onto the protein structure and allows functional sites to be readily identified upon visualization. The current version of ProSAT can be applied to large datasets of protein structures for fast visual identification of active and other functional sites derived from the SwissProt and Prosite databases.

How optimal are the binding energetics of barnase and barstar?

The extracellular ribonuclease barnase and its intracellular inhibitor barstar bind fast and with high affinity. Although extensive experimental and theoretical studies have been carried out on this system, it is unclear what the relative importance of different contributions to the high affinity is and whether binding can be improved through point mutations. In this work, we first applied Poisson-Boltzmann electrostatic calculations to 65 barnase-barstar complexes with mutations in both barnase and barstar.

Concerted simulations reveal how peroxidase compound III formation results in cellular oscillations.

A major problem in mathematical modeling of the dynamics of complex biological systems is the frequent lack of knowledge of kinetic parameters. Here, we apply Brownian dynamics simulations, based on protein three-dimensional structures, to estimate a previously undetermined kinetic parameter, which is then used in biochemical network simulations. The peroxidase-oxidase reaction involves many elementary steps and displays oscillatory dynamics important for immune response.

MolSurfer: A macromolecular interface navigator.

We describe the current status of the Java molecular graphics tool, MolSurfer. MolSurfer has been designed to assist the analysis of the structures and physico-chemical properties of macromolecular interfaces. MolSurfer provides a coupled display of two-dimensional (2D) maps of the interfaces generated with the ADS software and a three-dimensional (3D) view of the macromolecular structure in the Java PDB viewer, WebMol.

Biomolecular diffusional association.

The primary method for the computational study of biomolecular diffusional association is Brownian dynamics. Recent work has seen advances in the efficiency of computing association rates and in the accuracy of simulation models. New areas to which Brownian dynamics has been applied include protein polymerisation and protein adsorption to a surface.