Prediction of discrete water molecules preferentially bound to proteins and of water channels in protein interiors
Helmut Durchschlag Institute of Biophysics and Physical Biochemistry, University of Regensburg, Universitaetsstrasse 31, D-93040 Regensburg, Germany
Abstract:
Water molecules play a crucial role in behaviour and interactions of small molecules (ligands, receptors etc.) and proteins, because they exhibit various remarkable properties. Water molecules are small, polar, polarisable, and may form hydrogen-bonded networks; they have important influences on protein function and flexibility. Drug design and optimization rely on the computational prediction of the interactions between protein and ligand in aqueous environment. Therefore, molecular modelling of hydration represents a highly challenging aspect in the field of computational drug design [1]. Among the computational approaches applied recently, explicit inclusion of discrete water molecules was most effective. The presence of individual ordered waters in the calculations seems to improve the accuracy of predictions considerably. In ligand binding, the addition of water molecules can increase binding affinities significantly [2]. Unfortunately, even in high-resolution X-ray (or NMR) crystal structures of proteins only a small fraction of preferentially bound waters is identified, owing to insufficient resolution, inadequate discrimination between tightly and loosely bound waters, and incorrect hydrogen network building [3, 4]. Consequently, the prediction of a great many of discrete waters by a computational method is a grand challenge till date, in particular since consideration of both X-ray and predicted waters turned out to be the best scenario for de novo drug design computations.
In the case of proteins, usage of precise anhydrous 3D models (derived from atomic or amino acid coordinates or appropriate models) along with computation of the exact surface topography (molecular dot surface) and our recent hydration approaches (program HYDCRYST) allow the prediction of discrete water molecules preferentially bound to particular residues [5-8]. In this context, various approaches and procedural methods were tested: sequence of assignment to accessible residues, atomic vs. amino acid coordinates, original vs. coarse-grained models, fine-tuning of input parameters, variation of channel characteristics (e.g., width), rugosity effects. A critical comparison of the water sites on the surface, in active centres, ligand binding sites, crevices, interior, channels, contact areas etc. proves far-reaching identity of crystallographic data, if available, and our predictions. Examples presented include proteins ranging from simple to complex, multisubunit, liganded proteins and water-channels in membrane proteins (e.g., aquaporins) as well. Our hydration algorithms allow the prediction of the number and position of discrete water molecules, even in those cases where no crystallographic waters or water channels have been identified. Our approaches may be used in the future as useful tools for improving crystal data and for increasing the efficiency of rational drug design approaches.
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