A Path Planning Approach for Computing Large-Amplitude Motions of Flexible Molecules

Motivation: Motion is inherent to molecular interactions. Taking into account the molecular flexibility is necessary to develop accurate computational techniques for interaction pre-diction. Energy-based methods currently used in molecular modeling (i.e. molecular dynamics, Monte Carlo algorithms) are, in practice, only able to compute local motions. However, large-amplitude motions often occur in biological processes. We investigate the application of geometric path planning algo-rithms to compute such large motions on flexible molecular models. Our purpose is to exploit the efficacy of a geometric search as a filtering stage before refining with energies. Results: Two kinds of large-amplitude motions are treated in this paper: protein loop conformational changes (involving pro-tein backbone flexibility) and ligand trajectories to the active site of a protein (involving ligand and protein side-chain fle-xibility). The first simulations performed using our two-stage approach (geometry + energy) show that, compared to classi-cal molecular modeling methods, quite similar results can be obtained with a significant performance gain, ranging from 100 to 1000. Furthermore, the geometric treatment can provide by itself highly valuable information to biologists. Availability: The algorithms presented in this paper have been implemented in the general-purpose motion planning software Move3D (Siméon et al., 2001). We are currently working on an optimized stand alone library that will be available to the scientific community. Contact