Large‐scale comparison of protein essential dynamics from molecular dynamics simulations and coarse‐grained normal mode analyses

A large‐scale comparison of essential dynamics (ED) modes from molecular dynamic simulations and normal modes from coarse‐grained normal mode methods (CGNM) was performed on a dataset of 335 proteins. As CGNM methods, the elastic network model (ENM) and the rigid cluster normal mode analysis (RCNMA) were used. Low‐frequency normal modes from ENM correlate very well with ED modes in terms of directions of motions and relative amplitudes of motions. Notably, a similar performance was found if normal modes from RCNMA were used, despite a higher level of coarse graining. On average, the space spanned by the first quarter of ENM modes describes 84% of the space spanned by the five ED modes. Furthermore, no prominent differences for ED and CGNM modes among different protein structure classes (CATH classification) were found. This demonstrates the general potential of CGNM approaches for describing intrinsic motions of proteins with little computational cost. For selected cases, CGNM modes were found to be more robust among proteins that have the same topology or are of the same homologous superfamily than ED modes. In view of recent evidence regarding evolutionary conservation of vibrational dynamics, this suggests that ED modes, in some cases, might not be representative of the underlying dynamics that are characteristic of a whole family, probably due to insufficient sampling of some of the family members by MD. Proteins 2010. © 2010 Wiley‐Liss, Inc.     

Intrinsic molecular properties of the protein-protein bridge facilitate ratchet-like motion of the ribosome

The ribosomal intersubunit bridges maintain the overall architecture of the ribosome and thereby play a pivotal role in the dynamics of translation. The only protein-protein bridge, b1b, is formed by the two proteins, S13 and L5 of the small and large ribosomal subunits, respectively. B1b absorbs the largest movement during ratchet-like motion, and its two proteins reorganize in different constellations during this motion of the ribosome.Our results in this study of b1b in the Escherichia coli 70S ribosome suggest that the intrinsic molecular features of the bridging proteins allow the bridge to modulate the ratchet-like motion in a controlled manner. Additionally, another large subunit protein, L31, seems to participate with S13 and L5 in the formation, dynamics, and stabilization of this bridge.     

A Method for Measuring the Motion of Culture

ABSTRACT  Beginning with Edward Tylor's (1889) definition of culture as socially "acquired," I focus in this article on motion as social acquisition and transmission through "artifacts"—both durable (like ceramic pots) and fleeting (like sounds). Motion can be detected by comparison of the artifacts to which people are exposed with those they in turn produce. I examine rates of interaction with artifacts and changes in rates as evidence of the operation of "forces" such as interest and metaculture. I develop a set of axioms or laws of motion, growing out of fine-grained research on naturally occurring discourse, and endeavor to demonstrate their utility through application to three empirical cases. Although I deal with relatively small-scale artifacts, I conclude this article with the suggestion that its methods may prove useful in the broader study of cultural phenomena.     

Developmental instability: measures of resistance and resilience using pumpkin (Cucurbita pepo L.)

Fluctuating asymmetry measures random deviations from bilateral symmetry, and thus estimates developmental instability, the loss of ability by an organism to regulate its development. There have been few rigorous tests of this proposition. Regulation of bilateral symmetry must involve either feedback between the sides or independent regulation toward a symmetric set point. Either kind of regulation should decrease asymmetry over time, but only right–left feedback produces compensatory growth across sides, seen as antipersistent growth following perturbation. Here, we describe the developmental trajectories of perturbed and unperturbed leaves of pumpkin, Cucurbita pepo L., grown at three densities. Covering one side of a leaf with aluminium foil for 24 h perturbed leaf growth. Reduced growth on the perturbed side caused leaves to become more asymmetrical than unperturbed controls. After the treatment the size-corrected asymmetry decreased over time. In addition, rescaled range analysis showed that asymmetry was antipersistent rather than random, i.e. fluctuation in one direction was likely to be followed by fluctuations in the opposite direction. Development involves right–left feedback. This feedback reduced size-corrected asymmetry over time most strongly in the lowest density treatment suggesting that developmental instability results from a lack of resilience rather than resistance.   © 2003 The Linnean Society of London, Biological Journal of the Linnean Society , 2003, 78, 27–41.     

Modeling Vortex Swarming In Daphnia

Based on experimental observations in Daphnia, we introduce an agent-based model for the motion of single and swarms of animals. Each agent is described by a stochastic equation that also considers the conditions for active biological motion. An environmental potential further reflects local conditions for Daphnia, such as attraction to light sources. This model is sufficient to describe the observed cycling behavior of single Daphnia. To simulate vortex swarming of many Daphnia, i.e. the collective rotation of the swarm in one direction, we extend the model by considering avoidance of collisions. Two different ansatzes to model such a behavior are developed and compared. By means of computer simulations of a multi-agent system we show that local avoidance—as a special form of asymmetric repulsion between animals—leads to the emergence of a vortex swarm. The transition from uncorrelated rotation of single agents to the vortex swarming as a function of the swarm size is investigated. Eventually, some evidence of avoidance behavior in Daphnia is provided by comparing experimental and simulation results for two animals.     

Air movement preferences observed in office buildings

Office workers’ preferences for air movement have been extracted from a database of indoor environmental quality surveys performed in over 200 buildings. Dissatisfaction with the amount of air motion is very common, with too little air movement cited far more commonly than too much air movement. Workers were also surveyed in a detailed two-season study of a single naturally ventilated building. About one-half the building’s population wanted more air movement and only 4% wanted less. This same ratio applied when the air movement in workspaces was higher than 0.2 m/s, the de facto draft limit in the current ASHRAE and ISO thermal environment standards. Preference for “less air motion” exceeded that for “more” only at thermal sensations of −2 (cool) or colder. These results raise questions about the consequences of the ASHRAE and ISO standards’ restrictions on air movement, especially for neutral and warm conditions.     

Drug block of the hERG potassium channel: insight from modeling

Many commonly used, structurally diverse, drugs block the human ether-a-go-go-related gene (hERG) K(+) channel to cause acquired long QT syndrome, which can lead to sudden death via lethal cardiac arrhythmias. This undesirable side effect is a major hurdle in the development of safe drugs. To gain insight about the structure of hERG and the nature of drug block we have produced structural models of the channel pore domain, into each of which we have docked a set of 20 hERG blockers. In the absence of an experimentally determined three-dimensional structure of hERG, each of the models was validated against site-directed mutagenesis data. First, hERG models were produced of the open and closed channel states, based on homology with the prokaryotic K(+) channel crystal structures. The modeled complexes were in partial agreement with the mutagenesis data. To improve agreement with mutagenesis data, a KcsA-based model was refined by rotating the four copies of the S6 transmembrane helix half a residue position toward the C-terminus, so as to place all residues known to be involved in drug binding in positions lining the central cavity. This model produces complexes that are consistent with mutagenesis data for smaller, but not larger, ligands. Larger ligands could be accommodated following refinement of this model by enlarging the cavity using the inherent flexibility about the glycine hinge (Gly648) in S6, to produce results consistent with the experimental data for the majority of ligands tested.     

Local motions in a benchmark of allosteric proteins

Allosteric proteins have been studied extensively in the last 40 years, but so far, no systematic analysis of conformational changes between allosteric structures has been carried out. Here, we compile a set of 51 pairs of known inactive and active allosteric protein structures from the Protein Data Bank. We calculate local conformational differences between the two structures of each protein using simple metrics, such as backbone and side-chain Cartesian displacement, and torsion angle change and rearrangement in residue-residue contacts. Thresholds for each metric arise from distributions of motions in two control sets of pairs of protein structures in the same biochemical state. Statistical analysis of motions in allosteric proteins quantifies the magnitude of allosteric effects and reveals simple structural principles about allostery. For example, allosteric proteins exhibit substantial conformational changes comprising about 20% of the residues. In addition, motions in allosteric proteins show strong bias toward weakly constrained regions such as loops and the protein surface. Correlation functions show that motions communicate through protein structures over distances averaging 10-20 residues in sequence space and 10-20 A in Cartesian space. Comparison of motions in the allosteric set and a set of 21 nonallosteric ligand-binding proteins shows that nonallosteric proteins also exhibit bias of motion toward weakly constrained regions and local correlation of motion. However, allosteric proteins exhibit twice as much percent motion on average as nonallosteric proteins with ligand-induced motion. These observations may guide efforts to design flexibility and allostery into proteins.