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 the 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 * Corresponding author Email addresses: sjh@cmp.uea.ac.uk (Steven Hayward), s.laycock@uea.ac.uk (Stephen D. Laycock) Graphics and Modelling June 8, 2015 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. Preprint submitted to Journal of Molecular

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 us to study the binding process. Haptic-based docking provides an immersive virtual docking environment where the user can interact with and guide the molecules to their binding pose. Moreover, it allows human perception, intuition and knowledge to assist and accelerate the docking process, and reduces incorrect binding poses. Crucial for interactive docking is the real-time calculation of interaction forces. For smooth and accurate haptic exploration and manipulation, forcefeedback cues have to be updated at a rate of 1 kHz. Hence, force calculations must be performed within 1ms. To achieve this, modern haptic-based docking approaches often utilize pre-computed force grids and linear interpolation. However, such grids are time-consuming to pre-compute (especially for large molecules), memory hungry, can induce rough force transitions at cell boundaries and cannot be applied to flexible docking. Here we propose an efficient proximity querying method for computing intermolecular forces in real time. Our motivation is the eventual development of a haptic-based docking solution that can model molecular flexibility. Uniquely in a haptics application we use octrees to decompose the 3D search space in order to identify the set of interacting atoms within a cut-off distance. Force calculations are then performed on this set in real time. The implementation constructs the trees dynamically, and computes the interaction forces of large molecular structures (i.e. consisting of thousands of atoms) within haptic refresh rates. We have implemented this method in an immersive, haptic-based, rigid-body, molecular docking application called Haptimol RD. The user can use the haptic device to orientate the molecules in space, sense the interaction forces on the device, and guide the molecules to their binding pose. Haptimol RD is designed to run on consumer level hardware, i.e. there is no need for specialized/proprietary hardware.

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 utilising 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.

Interactive haptics-assisted docking provides a virtual environment for the study of molecular complex formation. It enables the user to interact with the virtual molecules, experience the interaction forces via their sense of touch, and gain insights about the docking process itself. Here we use a recently developed haptics software tool, Haptimol_RD, for the rigid docking of protein subunits to form complexes. Dimers, both homo and hetero, are loaded into the software with their subunits separated in space for the purpose of assessing whether they can be brought back into the correct docking pose via rigid-body movements. Four dimers were classified into two types: two with an interwinding subunit interface and two with a non-interwinding subunit interface. It was found that the two with an interwinding interface could not be docked whereas the two with the non-interwinding interface could be. For the two that could be docked a “sucking” effect could be felt on the haptic device when the correct binding pose was approached which is associated with a minimum in the interaction energy. It is clear that for those that could not be docked, the conformation of one or both of the subunits must change upon docking. This leads to the steric-based concept of a locked or non-locked interface. Non-locked interfaces have shapes that allow the subunits to come together or come apart without the necessity of intra-subunit conformational change, whereas locked interfaces require a conformational change within one or both subunits for them to be able to come apart.

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.