Haptic-assisted interactive molecular docking incorporating receptor flexibility

Haptic-assisted interactive docking tools immerse the user in an environment where intuition and knowledge can be used to help guide the docking process. Here we present such a tool where the user “holds” a rigid ligand via a haptic device through which they feel interaction forces with a flexible receptor biomolecule. To ensure forces transmitted through the haptic device are smooth and stable, they must be updated at a rate greater than 500 Hz. Due to this time constraint, the majority of haptic docking tools do not attempt to model the conformational changes that would occur when molecules interact during binding. Our haptic-assisted docking tool, “Haptimol Flexidock”, models a receptor’s conformational response to forces of interaction with a ligand whilst maintaining the required haptic refresh rate. In order to model receptor flexibility we use the method of linear response for which we determine the variance-covariance matrix of atomic fluctuations from the trajectory of an explicit-solvent Molecular Dynamics simulation of the ligand-free receptor molecule. Key to satisfying the time constraint is an eigenvector decomposition of the variance-covariance matrix which enables a good approximation to the conformational response of the receptor to be calculated rapidly. This exploits a feature of protein dynamics whereby most fluctuation occurs within a relatively small subspace. The method is demonstrated on Glutamine Binding Protein in interaction with glutamine, and Maltose Binding Protein in interaction with maltose. For both proteins, the movement that occurs when the ligand is docked near to its binding site matches the experimentally determined movement well. It is thought that this tool will be particularly useful for structure-based drug design

Review article: A comprehensive review of datasets and methodologies employed to produce thunderstorm climatologies

Thunderstorm and lightning climatological research is conducted with a view to increasing knowledge about the distribution of thunderstorm-related hazards and to gain an understanding of environmental factors increasing or decreasing their frequency. There are three main methodologies used in the construction of thunderstorm climatologies: Thunderstorm frequency, thunderstorm tracking or lightning flash density. These approaches utilise a wide variety of underpinning datasets and employ many different methods ranging from correlations with potential influencing factors and mapping the distribution of thunderstorm day frequencies to tracking individual thunderstorm cell movements. Meanwhile, lightning flash density climatologies are produced using lightning data alone, and these studies therefore follow a more standardised format. Whilst lightning flash density climatologies are primarily concerned with the occurrence of cloud-To-ground lightning, the occurrence of any form of lightning confirms the presence of a thunderstorm and can therefore be used in the compilation of a thunderstorm climatology. Regardless of approach, the choice of analysis method is heavily influenced by the coverage and quality (detection efficiency and location accuracy) of available datasets as well as by the controlling factors which are under investigation. The issues investigated must also reflect the needs of the end-use application to ensure that the results can be used effectively to reduce exposure to hazard, improve forecasting or enhance climatological understanding

High quality rendering of protein dynamics in space filling mode

Producing high quality depictions of molecular structures has been an area of academic interest for years, with visualisation tools such as UCSF Chimera, Yasara and PyMol providing a huge number of different rendering modes and lighting effects. However, no visualisation program supports per-pixel lighting effects with shadows whilst rendering a molecular trajectory in space filling mode. In this paper, a new approach to rendering high quality visualisations of molecular trajectories is presented. To enhance depth, ambient occlusion is included within the render. Shadows are also included to help the user perceive relative motions of parts of the protein as they move based on their trajectories. Our approach requires a regular grid to be constructed every time the molecular structure deforms allowing per-pixel lighting effects and ambient occlusion to be rendered every frame, at interactive refresh rates. Two different regular grids are investigated, a fixed grid and a memory efficient compact grid. The algorithms used allow trajectories of proteins comprising of up to 300,000 atoms in size to be rendered at ninety frames per second on a desktop computer using the GPU for general purpose computations. Regular grid construction was found to only take up a small proportion of the total time to render a frame. It was found that despite being slower to construct, the memory efficient compact grid outperformed the theoretically faster fixed grid when the protein being rendered is large, owing to its more efficient memory access patterns. The techniques described could be implemented in other molecular rendering software

Adding depth to overlapping displays can improve visual search performance

Standard models of visual search have focused upon asking participants to search for a single target in displays where the objects do not overlap one another, and where the objects are presented on a single depth plane. This stands in contrast to many everyday visual searches wherein variations in overlap and depth are the norm, rather than the exception. Here, we addressed whether presenting overlapping objects on different depths planes to one another can improve search performance. Across four different experiments using different stimulus types (opaque polygons, transparent polygons, opaque real-world objects, and transparent X-ray images), we found that depth was primarily beneficial when the displays were transparent, and this benefit arose in terms of an increase in response accuracy. Although the benefit to search performance only appeared in some cases, across all stimulus types, we found evidence of marked shifts in eye-movement behavior. Our results have important implications for current models and theories of visual search, which have not yet provided detailed accounts of the effects that overlap and depth have on guidance and object identification processes. Moreover, our results show that the presence of depth information could aid real-world searches of complex, overlapping displays

An Ultrasonically Actuated Needle Promotes the Transport of Nanoparticles and Fluids

Non-invasive therapeutic ultrasound methods, such as high-intensity focused ultrasound (HIFU), have limited access to tissue targets shadowed by bones or presence of gas. This study demonstrates that an ultrasonically actuated medical needle can be used to translate nanoparticles and fluids under the action of nonlinear phenomena, potentially overcoming some limitations of HIFU. A simulation study was first conducted to study the delivery of a tracer with an ultrasonically actuated needle (33 kHz) inside a porous medium acting as a model for soft tissue. The model was then validated experimentally in different concentrations of agarose gel showing a close match with the experimental results, when diluted soot nanoparticles (diameter < 150 nm) were employed as delivered entity. An additional simulation study demonstrated a threefold increase of the volume covered by the delivered agent in liver under a constant injection rate, when compared to without ultrasound. This method, if developed to its full potential, could serve as a cost effective way to improve safety and efficacy of drug therapies by maximizing the concentration of delivered entities within e.g. a small lesion, while minimizing exposure outside the lesion.Comment: 34 pages, 4 figures, under review in the Journal of the Acoustical Society of Americ

An Ultrasonically Actuated Fine-Needle Creates Cavitation in Bovine Liver

Ultrasonic cavitation is being used in medical applications as a way to influence matter, such as tissue or drug vehicles, on a micro-scale. Oscillating or collapsing cavitation bubbles provide transient mechanical force fields, which can, e.g., fractionate soft tissue or even disintegrate solid objects such as calculi. Our recent study demonstrates that an ultrasonically actuated medical needle can create cavitation phenomena inside water. However, the presence and behavior of cavitation and related bioeffects in diagnostic and therapeutic applications with ultrasonically actuated needles are not known. Using simulations, we demonstrate numerically and experimentally the cavitation phenomena near ultrasonically actuated needles. We define the cavitation onset within a liver tissue model with different total acoustic power levels. We directly visualize and quantitatively characterize cavitation events generated by the ultrasonic needle in thin fresh bovine liver sections enabled by high speed imaging. On a qualitative basis, the numerical and experimental results show a close resemblance in threshold and spatial distribution of cavitation. These findings are crucial for developing new methods and technologies employing ultrasonically actuated fine-needles such as ultrasound-enhanced fine-needle biopsy, drug delivery and histotripsy.Comment: 35 pages, 6 figures, under consideration at The Journal of the Acoustical Society of Americ