Fast and accurate grid representations for atom‐based docking with partner flexibility

Macromolecular docking methods can broadly be divided into geometric and atom‐based methods. Geometric methods use fast algorithms that operate on simplified, grid‐like molecular representations, while atom‐based methods are more realistic and flexible, but far less efficient. Here, a hybrid approach of grid‐based and atom‐based docking is presented, combining precalculated grid potentials with neighbor lists for fast and accurate calculation of atom‐based intermolecular energies and forces. The grid representation is compatible with simultaneous multibody docking and can tolerate considerable protein flexibility. When implemented in our docking method ATTRACT, grid‐based docking was found to be ∼35x faster. With the OPLSX forcefield instead of the ATTRACT coarse‐grained forcefield, the average speed improvement was >100x. Grid‐based representations may allow atom‐based docking methods to explore large conformational spaces with many degrees of freedom, such as multiple macromolecules including flexibility. This increases the domain of biological problems to which docking methods can be applied. © 2017 Wiley Periodicals, Inc.