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Structure (v.13, #3)

Macromolecular Assemblies Highlighted by Andrej Sali; Wah Chiu (pp. 339-341).
The functional units in cells are often assemblies of macromolecules, including proteins and nucleic acids. Therefore, the knowledge of structure, dynamics, and energetics of macromolecular complexes is necessary for a mechanistic description of biochemical and cellular processes. This special issue of Structure, “Macromolecular Assemblies Highlighted,� presents ten research articles and five reviews on the determination, representation, visualization, archival, and dissemination of assembly structure and dynamics.

Visual Methods from Atoms to Cells by David S. Goodsell (pp. 347-354).
Illustrations of molecular models are widely used for the study and dissemination of molecular structure and function. Several metaphors are commonly used to create these illustrations, and each captures a relevant aspect of the molecule and omits other aspects. Effective tools are available for rendering atomic structures by using several standard representations, and the research community is highly sophisticated in their use. Molecular properties, such as electrostatics, and large complex molecular and cellular systems currently pose challenges for representation.

Combining X-Ray Crystallography and Electron Microscopy by Michael G. Rossmann; Marc C. Morais; Petr G. Leiman; Wei Zhang (pp. 355-362).
The combination of cryo-electron microscopy to study large biological assemblies at low resolution with crystallography to determine near atomic structures of assembly fragments is quickly expanding the horizon of structural biology. This technique can be used to advantage in the study of large structures that cannot be crystallized, to follow dynamic processes, and to “purify� samples by visual selection of particles. Factors affecting the quality of cryo-electron microscopy maps and limits of accuracy in fitting known structural fragments are discussed.

Electron Cryomicroscopy of Biological Machines at Subnanometer Resolution by Wah Chiu; Matthew L. Baker; Wen Jiang; Matthew Dougherty; Michael F. Schmid (pp. 363-372).
Advances in electron cryomicroscopy (cryo-EM) have made possible the structural determination of large biological machines in the resolution range of 6–9 Å. Rice dwarf virus and the acrosomal bundle represent two distinct types of machines amenable to cryo-EM investigations at subnanometer resolutions. However, calculating the density map is only the first step, and much analysis remains to extract structural insights and the mechanism of action in these machines. This paper will review the computational and visualization methodologies necessary for analysis (structure mining) of the computed cryo-EM maps of these machines. These steps include component segmentation, averaging based on local symmetry among components, density connectivity trace, incorporation of bioinformatics analysis, and fitting of high-resolution component data, if available. The consequences of these analyses can not only identify accurately some of the secondary structure elements of the molecular components in machines but also suggest structural mechanisms related to their biological functions.

Usefulness and Limitations of Normal Mode Analysis in Modeling Dynamics of Biomolecular Complexes by Jianpeng Ma (pp. 373-380).
Various types of large-amplitude molecular deformation are ubiquitously involved in the functions of biological macromolecules, especially supramolecular complexes. They can be very effectively analyzed by normal mode analysis with well-established procedures. However, despite its enormous success in numerous applications, certain issues related to the applications of normal mode analysis require further discussion. In this review, the author addresses some common issues so as to raise the awareness of the usefulness and limitations of the method in the general community of structural biology.

Large Macromolecular Complexes in the Protein Data Bank: A Status Report by Shuchismita Dutta; Helen M. Berman (pp. 381-388).
The growing number of large macromolecular complexes in the Protein Data Bank (PDB) has warranted a closer look at these structures. An overview of the types of molecules that form these large complexes is presented here. Some of the challenges at the PDB in representing, archiving, visualizing, and analyzing these structures are discussed along with possible means to overcome them.

Fitting of High-Resolution Structures into Electron Microscopy Reconstruction Images by Felcy Fabiola,; Michael S. Chapman (pp. 389-400).
Dynamic macromolecular assemblies, such as ribosomes, viruses, and muscle protein complexes, are often more amenable to visualization by electron microscopy than by high-resolution X-ray crystallography or NMR. When high-resolution structures of component structures are available, it is possible to build an atomic model that gives information about the molecular interactions at greater detail than the experimental resolution, due to constraints of modeling placed upon the interpretation. There are now several competing computational methods to search systematically for orientations and positions of components that match the experimental image density, and continuing developments will be reviewed. Attention is now also moving toward the related task of optimization, with flexible and/or multifragment models and sometimes with stereochemically restrained refinement methods. This paper will review the various approaches and describe advances in the authors’ methods and applications of real-space refinement.

Molding Atomic Structures into Intermediate- Resolution Cryo-EM Density Maps of Ribosomal Complexes Using Real-Space Refinement by Haixiao Gao; Joachim Frank (pp. 401-406).
Real-space refinement has been previously introduced as a flexible fitting method to interpret medium-resolution cryo-EM density maps in terms of atomic structures. In this way, conformational changes related to functional processes can be analyzed on the molecular level. In the application of the technique to the ribosome, quasiatomic models have been derived that have advanced our understanding of translocation. In this article, the choice of parameters for the fitting procedure is discussed. The quality of the fitting depends critically on the number of rigid pieces into which the model is divided. Suitable quality indicators are crosscorrelation, R factor, and density residual, all of which can also be locally applied. The example of the ribosome may provide some guidelines for general applications of real-space refinement to flexible fitting problems.

Building the Atomic Model for the Bacterial Flagellar Filament by Electron Cryomicroscopy and Image Analysis by Koji Yonekura; Saori Maki-Yonekura; Keiichi Namba (pp. 407-412).
The bacterial flagellar filament is a helical propeller for bacterial locomotion. It is a well-ordered helical assembly of a single protein, flagellin, and its tubular structure is formed by 11 protofilaments, each in either of the two distinct conformations, L- and R-type, for supercoiling. We have been studying the three-dimensional structures of the flagellar filaments by electron cryomicroscopy and recently obtained a density map of the R-type filament up to 4 Å resolution from an image data set containing only about 41,000 molecular images. The density map showed the features of the α-helical backbone and some large side chains, which allowed us to build the complete atomic model as one of the first atomic models of macromolecules obtained solely by electron microscopy image analysis (). We briefly review the structure and the structure analysis, and point out essential techniques that have made this analysis possible.

Maturation Dynamics of Bacteriophage HK97 Capsid by A.J. Rader; Daniel H. Vlad; Ivet Bahar (pp. 413-421).
Maturation of the bacteriophage HK97 capsid requires a large conformational change of the virus capsid. Experimental studies have identified several intermediates along this maturation pathway. To gain insights into the molecular mechanisms of capsid maturation, we examined the fluctuation dynamics of the procapsid and mature capsid using a residue-level computational approach. The most cooperative motions of the procapsid are found to be consistent with the observed change in configuration that takes place during maturation. A few dominant modes of motion are sufficient to describe the anisotropic expansion that accompanies maturation. Based upon these modes, maturation is proposed to occur via an overall expansion and reconfiguration of the capsid initiated by puckering of the pentamers, followed by flattening and crosslinking of the hexameric subunits, and finally crosslinking of the pentameric subunits. The highly mobile E loops are stabilized by anchoring to highly stable residues belonging to neighboring subunits.

Morphological Characterization of Molecular Complexes Present in the Synaptic Cleft by Vladan Lucˇic´; Ting Yang; Gabriele Schweikert; Friedrich Förster; Wolfgang Baumeister (pp. 423-434).
We obtained tomograms of isolated mammalian excitatory synapses by cryo-electron tomography. This method allows the investigation of biological material in the frozen-hydrated state, without staining, and can therefore provide reliable structural information at the molecular level. We developed an automated procedure for the segmentation of molecular complexes present in the synaptic cleft based on thresholding and connectivity, and calculated several morphological characteristics of these complexes. Extensive lateral connections along the synaptic cleft are shown to form a highly connected structure with a complex topology. Our results are essentially parameter-free, i.e., they do not depend on the choice of certain parameter values (such as threshold). In addition, the results are not sensitive to noise; the same conclusions can be drawn from the analysis of both nondenoised and denoised tomograms.

Structural Characterization of Assemblies from Overall Shape and Subcomplex Compositions by Frank Alber; Michael F. Kim; Andrej Sali (pp. 435-445).
We suggest structure characterization of macromolecular assemblies by combining assembly shape determined by electron cyromicroscopy with information about subunit proximity determined by affinity purification. To achieve this aim, structure characterization is expressed as a problem in satisfaction of spatial restraints that (1) represents subunits as spheres, (2) encodes information about the subunit excluded volume, assembly shape, and pulldowns in a scoring function, and (3) finds subunit configurations that satisfy the input restraints by an optimization of the scoring function. Testing of the approach with model systems suggests its feasibility.

A Component-Based Software Environment for Visualizing Large Macromolecular Assemblies by Michel F. Sanner (pp. 447-462).
The interactive visualization of large biological assemblies poses a number of challenging problems, including the development of multiresolution representations and new interaction methods for navigating and analyzing these complex systems. An additional challenge is the development of flexible software environments that will facilitate the integration and interoperation of computational models and techniques from a wide variety of scientific disciplines. In this paper, we present a component-based software development strategy centered on the high-level, object-oriented, interpretive programming language: Python. We present several software components, discuss their integration, and describe some of their features that are relevant to the visualization of large molecular assemblies. Several examples are given to illustrate the interoperation of these software components and the integration of structural data from a variety of experimental sources. These examples illustrate how combining visual programming with component-based software development facilitates the rapid prototyping of novel visualization tools.

Compressed Representations of Macromolecular Structures and Properties by Chandrajit Bajaj; Julio Castrillon-Candas; Vinay Siddavanahalli; Zaiqing Xu (pp. 463-471).
We introduce a new and unified, compressed volumetric representation for macromolecular structures at varying feature resolutions, as well as for many computed associated properties. Important caveats of this compressed representation are fast random data access and decompression operations. Many computational tasks for manipulating large structures, including those requiring interactivity such as real-time visualization, are greatly enhanced by utilizing this compact representation. The compression scheme is obtained by using a custom designed hierarchical wavelet basis construction. Due to the continuity offered by these wavelets, we retain very good accuracy of molecular surfaces, at very high compression ratios, for macromolecular structures at multiple resolutions.

Software Extensions to UCSF Chimera for Interactive Visualization of Large Molecular Assemblies by Thomas D. Goddard; Conrad C. Huang; Thomas E. Ferrin (pp. 473-482).
Many structures of large molecular assemblies such as virus capsids and ribosomes have been experimentally determined to atomic resolution. We consider four software problems that arise in interactive visualization and analysis of large assemblies: how to represent multimers efficiently, how to make cartoon representations, how to calculate contacts efficiently, and how to select subassemblies. We describe techniques and algorithms we have developed and give examples of their use. Existing molecular visualization programs work well for single protein and nucleic acid molecules and for small complexes. The methods presented here are proposed as features to add to existing programs or include in next-generation visualization software to allow easy exploration of assemblies containing tens to thousands of macromolecules. Our approach is pragmatic, emphasizing simplicity of code, reliability, and speed. The methods described have been distributed as the Multiscale extension of the UCSF Chimera ( molecular graphics program.

Tangible Interfaces for Structural Molecular Biology by Alexandre Gillet; Michel Sanner; Daniel Stoffler; Arthur Olson (pp. 483-491).
The evolving technology of computer autofabrication makes it possible to produce physical models for complex biological molecules and assemblies. Augmented reality has recently developed as a computer interface technology that enables the mixing of real-world objects and computer-generated graphics. We report an application that demonstrates the use of autofabricated tangible models and augmented reality for research and communication in molecular biology. We have extended our molecular modeling environment, PMV, to support the fabrication of a wide variety of physical molecular models, and have adapted an augmented reality system to allow virtual 3D representations to be overlaid onto the tangible molecular models. Users can easily change the overlaid information, switching between different representations of the molecule, displays of molecular properties, or dynamic information. The physical models provide a powerful, intuitive interface for manipulating the computer models, streamlining the interface between human intent, the physical model, and the computational activity.
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