Interacting with the biomolecular solvent accessible surface via a haptic feedback device
© Stocks et al; licensee BioMed Central Ltd. 2009
Received: 3 August 2009
Accepted: 27 October 2009
Published: 27 October 2009
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.
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.
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.
The sense of touch can be used to augment our visual sense to gain a deeper insight into the three dimensional shapes of complex objects. Biomolecules are examples of highly complex three dimensional objects which are often visualised using molecular graphics. Many software programs exist which attempt to convey the three dimensional form of structures utilising stereoscopic viewing methods and depth cues. However, the augmentation of our sense of sight with touch would be a useful aid in understanding the overall three dimensional shape of a biomolecule and in particular the fine surface details that cannot easily be seen whilst visualising the molecule as a whole. With what should one "touch" a biomolecule?
Intuitively a sphere seems to be an obvious choice. Fortuitously, hard-sphere interactions between the biomolecule and a sphere of radius equal to an oxygen atom provides a reasonable model of solvent-solute interaction. Thus touching the biomolecular surface with a sphere the size of a water molecule one could also determine solvent-accessible regions of the biomolecule [1, 2]. Modelling touch requires a force-feedback or haptic device capable of exerting forces on the user. The process of determining the forces transmitted to the haptic device is known as haptic rendering and in this case works by computing forces of interaction between the probe, and the simulated biomolecule. This allows the user to feel the combined force acting on the probe.
In the area of biomolecular research the probe is usually a small molecule, known to interact with the biomolecule, where the forces are due to electrostatic and van-der-Waals interactions. The application of haptics to "molecular docking" has quite a long history with the first such project, GROPE1, starting in 1967 at the University of Carolina . Similar but more recent applications using personal computers allow the user to feel electrostatic forces between the probe molecule and the biomolecule [4, 5]. Up until recently these applications always assumed that both the protein and the ligand are completely rigid. However, "Interactive Molecular Dynamics" (IMD),  includes molecular flexibility by allowing the user to apply forces through a haptic device during a Molecular Dynamics simulation.
Our approach is quite different to previous applications of haptic rendering in the area of biomolecular simulation in that we aim to provide the user with a deeper appreciation of the complex three-dimensional shape of the molecule by combining a variety of graphical rendering techniques with haptic interactions. In the software a sphere, with a user-specified radius, is manipulated to interact with the chosen biomolecule. By using a probe sphere that is the same size as a water molecule, hard-sphere interactions with the biomolecule can be calculated to determine regions on the molecular surface that are accessible to water. In that sense our application could be called "Interactive Solvent-Accessible Surface" (ISAS).
To allow a probe sphere to be used with a user-specified radius the above single point algorithm need not be modified. Instead, the van der Waals radius of every atom is enlarged by the radius of the probe sphere. The single point haptic rendering algorithm then utilises the enlarged representation whilst the spherical probe and original molecule are displayed to the user. To achieve the interactive accessible surface simulation a probe sphere with a radius equal to the van der Waals radius of an oxygen atom can be created and centered at the location of the HIP. The force returned through the haptic device is designed to mimic the resulting hard sphere interactions between the probe and the contacting atoms on the biomolecule. The effect is to see and feel the water probe roll around over the hard surface of the biomolecule. In order to visually guide the user to regions on the biomolecular surface known to bind water molecules, crystallographic water molecules are rendered graphically but not haptically meaning they can be seen but not felt. Crystallographic water molecules are visualized as semi-opaque spheres through the use of alpha blending. These are referred to as "ghost water". To guide the user to specific residues or ligands the user can select from a variety of colours not contained within the CPK colour system and assign these to residues selected by residue number and chain identifier.
Liver Alcohol Dehydrogenase
A haptic rendering application for biomolecular visualisation has been developed that allows one to gain three-dimensional awareness of the shape of a biomolecule. By using a water molecule as the probe, the process of exploration has the further benefit of being able to determine regions on the molecular surface that are accessible to the solvent. Aside from the simultaneous three-dimensional insight into the shape of the molecule, what other advantage would this method have over standard solvent-accessible surface area calculations? One obvious advantage is that one can easily appreciate the dimensions of a channel and the number of water molecules that would fit through it. Another advantage is that the accessibility of a channel or cavity can be appreciated. A cavity with an opening where the user has difficulty in maneuvering a water molecule could indicate an entropic bottleneck. In addition, placing the probe coincident with crystallographic water molecules gave the distinct impression that these are located within small pockets that provide a sterically stable environment for water molecules. None of this information would be directly attainable from standard solvent-accessible surface area calculations. It is clear that our approach has the limitation of not accurately modelling interactions and response due to flexibility that occurs when a water molecule approaches a biomolecule. Reduction of the probe radius could be used to model the effects of flexibility in a simple way. A better alternative would be to use the tool to compare accessilibility to channels and cavities in conformations generated from Molecular Dynamics simulations.
Haptic rendering combined with molecular graphics allows the user to feel as well as see a complex three-dimensional object. In its application to biomolecular modelling it allows one to not only gain insight into the shape of a biomolecule, but by using a spherical probe equivalent in size to a water molecule, it also allows one to explore the solvent accessible surface interactively by rolling the probe over the molecule. Although many of the insights into cavity shape may be gained by purely graphical techniques, usage of the system has shown that it allows the user to assess the difficulty water molecules may have in accessing or escaping a cavity through the difficulty the user has in manoeuvring the probe through a constriction.
This would not be easily appreciated through purely graphical techniques.
Availability and Requirements
Project Name: HaptiMol ISAS
Project Home Page: http://www.haptimol.co.uk
Operating System(s): Windows 2000, XP, Vista 32bit, Vista 64bit
Programming Language: C++
Other Requirements: OpenGL version 2.0 or later is required for high quality rendering. However, if a lower version is detected the program will adjust the rendering algorithm accordingly. The software supports all Phantom Haptic Feedback Devices (Phantom Omni, Phantom Premium, Phantom Premium 6DOF and Phantom Desktop). OpenHaptics Software (Academic Edition) is available for free download.
Any restrictions to use by non-academics: The current release is for non-commercial use only.
List of Abbreviations Used
Haptic Interface Point
- The virtual end point of the haptic device:
this point is not visible to the user. SCP: Surface Contact Point
- The point calculated in the surface tracking algorithm:
this point is visible to the user. LADH: Horse Liver Alcohol Dehydrogenase
β-methylene-selenazole-4-2 carboxyamide-adenine dinucleotide
nicotinamide adenine dinucleotide.
The authors wish to thank all the researchers who have been involved with testing of the software and for their suggestions for improvements, most of which are now included in the software.
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