Docking of ATP to Ca-ATPase: considering protein domain motions

Most standard molecular docking algorithms take into account only ligand flexibility, while numerous studies demonstrate that receptor flexibility may be also important. While some efficient methods have been proposed to take into account local flexibility of protein side chains, the influence of large-scale domain motions on the docking results still represents a challenge for computational methods. In this work we compared the results of ATP docking to different models of Ca-ATPase: crystallographic apo- and holo-forms of the enzyme as well as "flexible" target models generated via molecular dynamics (MD) simulations in water. MD simulations were performed for two different apo-forms and one holo-form of Ca2+-ATPase and reveal large-scale domain motions of type "closure", which is consistent with experimental structures. Docking to a set of MD-conformers yielded correct solutions with ATP bound in both domains regardless of the starting Ca2+-ATPase structure. Also, special attention was paid to proper ranking of docking solutions and some particular features of different scoring functions and their applicability for the model of "flexible" receptor. Particularly, the results of docking ATP were ranked by a scoring criterion specially designed to estimate ATP-protein interactions. This criterion includes stacking and hydrophobic interactions characteristic of ATP-protein complexes. The performance of this ligand-specific scoring function was considerably better than that of a standard scoring function used in the docking algorithm.