Simulating molecular docking with haptics

Intermolecular binding underlies various metabolic and regulatory processes of the cell, and the therapeutic and pharmacological properties of drugs. Molecular docking systems model and simulate these interactions in silico and allow the study of the binding process. In molecular docking, haptics enables the user to sense the interaction forces and intervene cognitively in the docking process. Haptics-assisted docking systems provide an immersive virtual docking environment where the user can interact with the molecules, feel the interaction forces using their sense of touch, identify visually the binding site, and guide the molecules to their binding pose. Despite a forty-year research e�ort however, the docking community has been slow to adopt this technology. Proprietary, unreleased software, expensive haptic hardware and limits on processing power are the main reasons for this. Another signi�cant factor is the size of the molecules simulated, limited to small molecules. The focus of the research described in this thesis is the development of an interactive haptics-assisted docking application that addresses the above issues, and enables the rigid docking of very large biomolecules and the study of the underlying interactions. Novel methods for computing the interaction forces of binding on the CPU and GPU, in real-time, have been developed. The force calculation methods proposed here overcome several computational limitations of previous approaches, such as precomputed force grids, and could potentially be used to model molecular exibility at haptic refresh rates. Methods for force scaling, multipoint collision response, and haptic navigation are also reported that address newfound issues, particular to the interactive docking of large systems, e.g. force stability at molecular collision. The i ii result is a haptics-assisted docking application, Haptimol RD, that runs on relatively inexpensive consumer level hardware, (i.e. there is no need for specialized/proprietary hardware)

Interactive molecular docking with haptics and advanced graphics

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