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)

A real-time proximity querying algorithm for haptic-based molecular docking

Intermolecular binding underlies every 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, force-feedback 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

Software Introduction: Methodological advances for interacting with biomolecules using haptics

Over the past 15 years we have been developing tools for interacting with biomolecules using haptics. Interactions with biomolecules in the virtual world are made via a haptic-feedback device that is able to resist inputs from the user or even act to move the user’s hand in response to molecular forces. Here we highlight the key methodological advances made in the development of these tools including Haptimol ISAS, a tool for interacting with a molecule’s solvent accessible surface, Haptimol ENM, a tool for applying forces to an elastic network model of a biomolecule, DockIT (formerly Haptimol RD), for interactive rigid docking, and Haptimol FlexiDock, for interactive docking that models flexibility in the receptor molecule

GPU-accelerated Cartoon Representation for Interactive Flexible Docking

Molecular docking involves simulating the binding of two biomolecules, a receptor and ligand, and is widely used for structurebased drug design. There are two main types of docking tools: automated and interactive. While automated tools are useful for reducing the search space of ligands and identifying potential binding sites, interactive tools allow the user to guide the docking process and observe what happens during docking. High computation speeds are required for interactive docking to handle both protein deformation and user interaction in real time. The cartoon representation, not to be confused with cartoon style rendering, is a protein representation that shows an abstracted view and is frequently used by structural biologists to not only identify a protein, but also to identify key regions within a protein of interest. There are examples of GPU-accelerated methods to construct the cartoon representation in real time. However, none of these methods achieve real-time assignment of secondary structure and construction of the cartoon representation for a flexible molecule. This paper presents our method to achieve this, integrated into an interactive docking tool with receptor flexibility. The methods outlined in this paper produced some promising results, with proteins of up to 3,300 amino acid residues being constructed and rendered at 70 fps

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 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

Protein domain movement involved in binding of belinostat and HPOB as inhibitors of histone deacetylase 6 (HDAC6): a hybrid automated-interactive docking study

DockIT is a tool for interactive molecular docking that can model both the local and global conformational response of the receptor to the docking of a ligand based on information from a molecular dynamics simulation. Using DockIT we have investigated the binding process of two histone deacetylase (HDAC) inhibitors to HDAC6: the nonselective approved drug belinostat and the preclinical HPOB. To model HDAC6’s conformational response to the binding of the inhibitors we performed a 200-nanosecond explicit-solvent molecular dynamics simulation on HDAC6. Unexpectedly the simulation revealed a domain movement that affects the size and shape of the binding pocket. Using automated docking and a rigid model for the inhibitors, the domain movement continuously adapts the pocket to the presence of the inhibitor. For both inhibitors, an intermediate binding site was found where it was partially inserted, with a hydrogen bond formed between the inhibitor’s hydroxamic acid and the Tyr745 side chain. Pushing the inhibitor deeper into the pocket over an energy barrier and re-engaging automated docking, a final binding pose resulted with a root-mean square deviation with its respective crystallographic pose of 1.0 Å for belinostat and 1.4 Å for HPOB. We believe our results mimic substrate recognition by the enzyme, with an initial partial binding of the acetyllysine residue with Tyr745. During binding a relay of hydrogen bonds occurs coordinating the orientation of the cap and the hydroxamic acid inside the pocket. The interaction between the cap and the surface of HDAC6 explains the reason for the hydroxamic acid warhead in HPOB binding in a flipped orientation compared to belinostat

The impact of electronic versus paper-based data capture on data collection logistics and on missing scores in thyroid cancer patients

Purpose The purpose of this study was to investigate the impact of the type of data capture on the time and help needed for collecting patient-reported outcomes as well as on the proportion of missing scores. Methods In a multinational prospective study, thyroid cancer patients from 17 countries completed a validated questionnaire measuring quality of life. Electronic data capture was compared to the paper-based approach using multivariate logistic regression. Results A total of 437 patients were included, of whom 13% used electronic data capture. The relation between data capture and time needed was modified by the emotional functioning of the patients. Those with clinical impairments in that respect needed more time to complete the questionnaire when they used electronic data capture compared to paper and pencil (ORadj 24.0; p = 0.006). This was not the case when patients had sub-threshold emotional problems (ORadj 1.9; p = 0.48). The odds of having the researcher reading the questions out (instead of the patient doing this themselves) (ORadj 0.1; p = 0.01) and of needing any help (ORadj 0.1; p = 0.01) were lower when electronic data capture was used. The proportion of missing scores was equivalent in both groups (ORadj 0.4, p = 0.42). Conclusions The advantages of electronic data capture, such as real-time assessment and fewer data entry errors, may come at the price of more time required for data collection when the patients have mental health problems. As this is not uncommon in thyroid cancer, researchers need to choose the type of data capture wisely for their particular research question

Determination of locked interfaces in biomolecular complexes using Haptimol_RD

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 flexible-receptor molecular docking in VR using DockIT

Interactive docking enables the user to guide and control the docking of two biomolecules into a binding pose. It is of use when a 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 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

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 500 Hz to 1 kHz. 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 2 ms 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