Abstract

Many biological activities take place through the physicochemical interaction of two molecules. This interaction occurs when one of the molecules finds a suitable location on the surface of the other for binding. This process is known as molecular docking, and it has applications to drug design. If we can determine which drug molecule binds to a particular protein, and how the protein interacts with the bonded molecule, we can possibly enhance or inhibit its activities. This information, in turn, can be used to develop new drugs that are more effective against diseases. In this paper, we propose a new approach based on a human-computer interaction paradigm for the solution of the rigid body molecular docking problem. In our approach, a rigid ligand molecule (i.e., drug) manipulated by the user is inserted into the cavities of a rigid protein molecule to search for the binding cavity, while the molecular interaction forces are conveyed to the user via a haptic device for guidance. We developed a new visualization concept, Active Haptic Workspace (AHW), for the efficient exploration of the large protein surface in high resolution using a haptic device having a small workspace. After the discovery of the true binding site and the rough alignment of the ligand molecule inside the cavity by the user, its final configuration is calculated off-line through time stepping molecular dynamics (MD) simulations. At each time step, the optimum rigid body transformations of the ligand molecule are calculated using a new approach, which minimizes the distance error between the previous rigid body coordinates of its atoms and their new coordinates calculated by the MD simulations. The simulations are continued until the ligand molecule arrives at the lowest energy configuration. Our experimental studies conducted with six human subjects testing six different molecular complexes demonstrate that given a ligand molecule and five potential binding sites on a protein surface, the subjects can successfully identify the true binding site using visual and haptic cues. Moreover, they can roughly align the ligand molecule inside the binding cavity such that the final configuration of the ligand molecule can be determined via the proposed MD simulations.

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