Biomolecular interactions underpin many of the processes that make up life. Molecular docking is the study of these interactions in silico. Interactive docking applications put the user in control of the docking process, allowing them to use their knowledge and intuition to determine how molecules bind together.
Interactive molecular docking applications often use haptic devices as a method of controlling the docking process. These devices allow the user to easily manipulate the structures in 3D space, whilst feeling the forces that occur in response to their manipulations. As a result of the force refresh rate requirements of haptic devices, haptic assisted docking applications are often limited, in that they model the interacting proteins as rigid, use low fidelity visualisations or require expensive propriety equipment to use.
The research in this thesis aims to address some of these limitations. Firstly, the development of a visualisation algorithm capable of rendering a depiction of a deforming protein at an interactive refresh rate, with per-pixel shadows and ambient occlusion, is discussed. Then, a novel approach to modelling molecular flexibility whilst maintaining a stable haptic refresh rate is developed.
Together these algorithms are presented within Haptimol FlexiDock, the first haptic-assisted molecular docking application to support receptor flexibility with high fidelity graphics, whilst also maintaining interactive refresh rates on both the haptic device and visual display. Using Haptimol FlexiDock, docking experiments were performed between two protein-ligand pairs: Maltodextrin Binding Protein and Maltose, and glutamine Binding Protein and Glucose. When the ligand was placed in its approximate binding site, the direction of over 80% of the intra-molecular movement aligned with that seen in the experimental structures.
Furthermore, over 50% of the expected backbone motion was present in the structures generated with FlexiDock. Calculating the deformation of a biomolecule in real time, whilst maintaining an interactive refresh rate on the haptic device (> 500Hz) is a breakthrough in the field of interactive molecular docking, as, previous approaches either model protein flexibility, but fail to achieve the required haptic refresh rate, or do not consider biomolecular flexibility at all
