Haptic-Assisted Interactive Molecular Docking Incorporating Receptor Flexibility

Abstract

Haptic-assisted interactive docking tools immerse the user in an environment where intuition and knowledge can be used to help guide the docking process. Here we present such a tool where the user "holds" a rigid ligand via a haptic device through which they feel interaction forces with a flexible receptor biomolecule. To ensure forces transmitted through the haptic device are smooth and stable, they must be updated at a rate greater than 500 Hz. Due to this time constraint, the majority of haptic docking tools do not attempt to model the conformational changes that would occur when molecules interact during binding. Our haptic-assisted docking tool, "Haptimol FlexiDock", models a receptor's conformational response to forces of interaction with a ligand whilst maintaining the required haptic refresh rate. In order to model receptor flexibility we use the method of linear response for which we determine the variance-covariance matrix of atomic fluctuations from the trajectory of an explicit-solvent Molecular Dynamics simulation of the ligand-free receptor molecule. Key to satisfying the time constraint is an eigenvector decomposition of the variance-covariance matrix which enables a good approximation to the conformational response of the receptor to be calculated rapidly. This exploits a feature of protein dynamics whereby most fluctuation occurs within a relatively small subspace. The method is demonstrated on Glutamine Binding Protein in interaction with glutamine, and Maltose Binding Protein in interaction with maltose. For both proteins the movement that occurs when the ligand is docked near to its binding site matches the experimentally determined movement well. It is thought that this tool will be particularly useful for structure-based drug design.

Interactive Flexible-Receptor Molecular Docking in Virtual Reality Using DockIT

“…One also needs to supply the coordinates of the relaxed structure, boldr boldo , loaded as the “Receptor” at the start of a DockIT session, here the “closest to average” structure from the MD trajectory. Further details are provided in the article describing the Haptimol FlexiDock prototype and the user manual.…”

“…We also discuss a method to rapidly calculate hydrogen bonds between the receptor and ligand molecules and techniques to rapidly render graphical representations of the molecules, including ball-and-stick, backbone, space-filling, and molecular surface. Its most unique feature is the ability to model receptor flexibility using the method of linear response which in contrast to IMD results in a smooth, time-averaged response …”

Wielding the power of interactive molecular simulations

“…49,[135][136][137] Interactive docking can also be considered a challenging use case of model building and was used early on for rigid 24 or flexible docking. 138 This has led to the development of dedicated interactive software tools such as Dock-ingShop 139 or Haptimol FlexiDock 106 and some success stories. 72,140…”

A computational method to simulate global conformational changes of proteins induced by cosolvent

“…In their method, the structural change of a protein due to the ligand binding is described as a response by atomic fluctuations in the ligand unbinding state and ligand–protein interactions. Following them, several computational methods have been proposed based on the LRT 12–18 …”