Interactive Flexible-Receptor Molecular Docking in Virtual Reality Using DockIT.

Interactive docking enables the user to guide and control the docking of two biomolecules into a binding pose. It is of particular use when the binding site is known and is thought to be applicable to structure-based drug design (SBDD) and educating students about biomolecular interactions. For SBDD, it enables expertise and intuition to be brought to bear in the drug design process. In education, it can teach students about the most basic level of biomolecular function. Here, we introduce DockIT for virtual reality (VR) that uses a VR headset and hand-held controllers. Using the method of linear response on explicit solvent molecular dynamics simulations, DockIT can model both global and local conformational changes within the receptor due to forces of interaction with the ligand. It has real-time flexible molecular surface rendering and can show the real-time formation and breaking of hydrogen bonds, both between the ligand and receptor and within the receptor itself as it smoothly changes conformation.

DockIT: a tool for interactive molecular docking and molecular complex construction.

SUMMARY: DockIT is a tool that has a unique set of physical and graphical features for interactive molecular docking. It enables the user to bring a ligand and a receptor into a docking pose by controlling relative position and orientation, either with a mouse and keyboard, or with a haptic device. Atomic interactions are modelled using molecular dynamics-based force-fields with the force on the ligand being felt on a haptic device. Real-time calculation and display of intermolecular hydrogen bonds and multipoint collision detection either using maximum force or maximum atomic overlap, mean that together with the ability to monitor selected intermolecular atomic distances, the user can find physically feasible docking poses that satisfy distance constraints derived from experimental methods. With these features and the ability to output and reload docked structures it can be used to accurately build up large multi-component molecular systems in preparation for molecular dynamics simulation. AVAILABILITY AND IMPLEMENTATION: DockIT is available free of charge for non-commercial use at http://www.haptimol.co.uk/downloads.htm. It requires a windows computer with GPU that supports OpenCL 1.2 and OpenGL 4.0. It may be used with a mouse and keyboard, or a haptic device from 3DSystems.

Virtual Environment for Studying the Docking Interactions of Rigid Biomolecules with Haptics.

Haptic technology facilitates user interaction with the virtual world via the sense of touch. In molecular docking, haptics enables the user to sense the interaction forces during the docking process. Here we describe a haptics-assisted interactive software tool, called Haptimol_RD, for the study of docking interactions. By utilizing GPU-accelerated proximity querying methods very large systems can now be studied. Methods for force scaling, multipoint collision response and haptic navigation are described that address force stability issues that are particular to the interactive docking of large systems. Thus, Haptimol_RD expands, for the first time, the use of interactive biomolecular haptics to the study of protein-protein interactions. Unlike existing approaches, Haptimol_RD is designed to run on relatively inexpensive consumer-level hardware and is freely available to the community.

Adaptive GPU-accelerated force calculation for interactive rigid molecular docking using haptics.

Molecular docking systems model and simulate in silico the interactions of intermolecular binding. Haptics-assisted docking enables the user to interact with the simulation via their sense of touch but a stringent time constraint on the computation of forces is imposed due to the sensitivity of the human haptic system. To simulate high fidelity smooth and stable feedback the haptic feedback loop should run at rates of 500Hz to 1kHz. We present an adaptive force calculation approach that can be executed in parallel on a wide range of Graphics Processing Units (GPUs) for interactive haptics-assisted docking with wider applicability to molecular simulations. Prior to the interactive session either a regular grid or an octree is selected according to the available GPU memory to determine the set of interatomic interactions within a cutoff distance. The total force is then calculated from this set. The approach can achieve force updates in less than 2ms for molecular structures comprising hundreds of thousands of atoms each, with performance improvements of up to 90 times the speed of current CPU-based force calculation approaches used in interactive docking. Furthermore, it overcomes several computational limitations of previous approaches such as pre-computed force grids, and could potentially be used to model receptor flexibility at haptic refresh rates.

3D printing of an aortic aneurysm to facilitate decision making and device selection for endovascular aneurysm repair in complex neck anatomy.

PURPOSE: To describe rapid prototyping or 3-dimensional (3D) printing of aneurysms with complex neck anatomy to facilitate endovascular aneurysm repair (EVAR). CASE REPORT: A 75-year-old man had a 6.6-cm infrarenal aortic aneurysm that appeared on computed tomographic angiography to have a sharp neck angulation of ~90°. However, although the computed tomography (CT) data were analyzed using centerline of flow, the true neck length and relations of the ostial origins were difficult to determine. No multidisciplinary consensus could be reached as to which stent-graft to use owing to these borderline features of the neck anatomy. Based on past experience with rapid prototyping technology, a decision was taken to print a model of the aneurysm to aid in visualization of the neck anatomy. The CT data were segmented, processed, and converted into a stereolithographic format representing the lumen as a 3D volume, from which a full-sized replica was printed within 24 hours. The model demonstrated that the neck was adequate for stent-graft repair using the Aorfix device. CONCLUSION: Rapid prototyping of aortic aneurysms is feasible and can aid decision making and device delivery. Further work is required to test the value of 3D replicas in planning procedures and their impact on procedure time, radiation dose, and procedure cost.

Fast reconstructed radiographs from octree-compressed volumetric data.

PURPOSE: Simulated 2D X-ray images called digitally reconstructed radiographs (DRRs) have important applications within medical image registration frameworks where they are compared with reference X-rays or used in implementations of digital tomosynthesis (DTS). However, rendering DRRs from a CT volume is computationally demanding and relatively slow using the conventional ray-casting algorithm. Image-guided radiation therapy systems using DTS to verify target location require a large number DRRs to be precomputed since there is insufficient time within the automatic image registration procedure to generate DRRs and search for an optimal pose. METHOD: DRRs were rendered from octree-compressed CT data. Previous work showed that octree-compressed volumes rendered by conventional ray casting deliver a registration with acceptable clinical accuracy, but efficiently rendering the irregular grid of an octree data structure is a challenge for conventional ray casting. We address this by using vertex and fragment shaders of modern graphics processing units (GPUs) to directly project internal spaces of the octree, represented by textured particle sprites, onto the view plane. The texture is procedurally generated and depends on the CT pose. RESULTS: The performance of this new algorithm was found to be 4 times faster than that of a ray-casting algorithm implemented using NVIDIA™Compute Unified Device Architecture (CUDA™) on an equivalent GPU (~95 % octree compression). Rendering artifacts are apparent (consistent with other splatting algorithm), but image quality tends to improve with compression and fewer particles are needed. A peak signal-to-noise ratio analysis confirmed that the images rendered from compressed volumes were of marginally better quality to those rendered using Gaussian footprints. CONCLUSIONS: Using octree-encoded DRRs within a 2D/3D registration framework indicated the approach may be useful in accelerating automatic image registration.

GPU accelerated generation of digitally reconstructed radiographs for 2-D/3-D image registration.

Recent advances in programming languages for graphics processing units (GPUs) provide developers with a convenient way of implementing applications which can be executed on the CPU and GPU interchangeably. GPUs are becoming relatively cheap, powerful, and widely available hardware components, which can be used to perform intensive calculations. The last decade of hardware performance developments shows that GPU-based computation is progressing significantly faster than CPU-based computation, particularly if one considers the execution of highly parallelisable algorithms. Future predictions illustrate that this trend is likely to continue. In this paper, we introduce a way of accelerating 2-D/3-D image registration by developing a hybrid system which executes on the CPU and utilizes the GPU for parallelizing the generation of digitally reconstructed radiographs (DRRs). Based on the advancements of the GPU over the CPU, it is timely to exploit the benefits of many-core GPU technology by developing algorithms for DRR generation. Although some previous work has investigated the rendering of DRRs using the GPU, this paper investigates approximations which reduce the computational overhead while still maintaining a quality consistent with that needed for 2-D/3-D registration with sufficient accuracy to be clinically acceptable in certain applications of radiation oncology. Furthermore, by comparing implementations of 2-D/3-D registration on the CPU and GPU, we investigate current performance and propose an optimal framework for PC implementations addressing the rigid registration problem. Using this framework, we are able to render DRR images from a 256×256×133 CT volume in ~24 ms using an NVidia GeForce 8800 GTX and in ~2 ms using NVidia GeForce GTX 580. In addition to applications requiring fast automatic patient setup, these levels of performance suggest image-guided radiation therapy at video frame rates is technically feasible using relatively low cost PC architecture.

3-D printout of a DICOM file to aid surgical planning in a 6 year old patient with a large scapular osteochondroma complicating congenital diaphyseal aclasia.

A 6 year old girl presented with a large osteochondroma arising from the scapula. Radiographs, CT and MRI were performed to assess the lesion and to determine whether the lesion could be safely resected. A model of the scapula was created by post-processing the DICOM file and using a 3-D printer. The CT images were segmented and the images were then manually edited using a graphics tablet, and then an STL-file was generated and a 3-D plaster model printed. The model allowed better anatomical understanding of the lesion and helped plan surgical management.

Interacting with the biomolecular solvent accessible surface via a haptic feedback device.

BACKGROUND: From the 1950s computer based renderings of molecules have been produced to aid researchers in their understanding of biomolecular structure and function. A major consideration for any molecular graphics software is the ability to visualise the three dimensional structure of the molecule. Traditionally, this was accomplished via stereoscopic pairs of images and later realised with three dimensional display technologies. Using a haptic feedback device in combination with molecular graphics has the potential to enhance three dimensional visualisation. Although haptic feedback devices have been used to feel the interaction forces during molecular docking they have not been used explicitly as an aid to visualisation. RESULTS: A haptic rendering application for biomolecular visualisation has been developed that allows the user to gain three-dimensional awareness of the shape of a biomolecule. By using a water molecule as the probe, modelled as an oxygen atom having hard-sphere interactions with the biomolecule, the process of exploration has the further benefit of being able to determine regions on the molecular surface that are accessible to the solvent. This gives insight into how awkward it is for a water molecule to gain access to or escape from channels and cavities, indicating possible entropic bottlenecks. In the case of liver alcohol dehydrogenase bound to the inhibitor SAD, it was found that there is a channel just wide enough for a single water molecule to pass through. Placing the probe coincident with crystallographic water molecules suggests that they are sometimes located within small pockets that provide a sterically stable environment irrespective of hydrogen bonding considerations. CONCLUSION: By using the software, named HaptiMol ISAS (available from http://www.haptimol.co.uk), one can explore the accessible surface of biomolecules using a three-dimensional input device to gain insights into the shape and water accessibility of the biomolecular surface that cannot be so easily attained using conventional molecular graphics software.