Ligand docking is a widely used tool for lead discovery and binding mode prediction based drug discovery. The greatest challenges in docking occur when the receptor significantly reorganizes upon small molecule binding, thereby requiring an induced fit docking (IFD) approach in which the receptor is allowed to move in order to bind to the ligand optimally. IFD methods have had some success but suffer from a lack of reliability. Complementing IFD with all-atom molecular dynamics (MD) is a straightforward solution in principle but not in practice due to the severe time scale limitations of MD. Here we introduce a metadynamics plus IFD strategy for accurate and reliable prediction of the structures of protein-ligand complexes at a practically useful computational cost. Our strategy allows treating this problem in full atomistic detail and in a computationally efficient manner and enhances the predictive power of IFD methods. We significantly increase the accuracy of the underlying IFD protocol across a large data set comprising 42 different ligand-receptor systems. We expect this approach to be of significant value in computationally driven drug design.

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Proton solvation properties and transport mechanisms have been studied in hydrated Nafion using the self-consistent multistate empirical valence bond (SCI-MS-EVB) method that includes the effects excess proton charge defect delocalization and Grotthuss proton hopping. It was found that sulfonate groups influence excess proton solvation, as well as the proton hydration structure, by stabilizing a more Zundel-like (H(5)O(2)(+)) structure in their first solvation shells. Hydrate proton-related hydrogen bond networks were observed to be more stable than networks with water alone. Diffusion rates, Arrhenius activation energies, and transport pathways were calculated and analyzed to characterize the nature of the proton transport. Diffusion rate analysis suggests that a proton-hopping mechanism dominates the proton transport for the studied water loading levels and that there is a clear degree of anticorrelation with the vehicular transport. The activation energy drops quickly with an increasing water content when the water loading level is smaller than ∼10 H(2)O/SO(3)(-), which is consistent with experimental observations. The sulfonate groups were also found to affect the proton hopping directions. The temperature and water content effects on the proton transport pathways were also investigated.

The effective force coarse-graining (EF-CG) method was applied to the imidazolium-based nitrate ionic liquids with various alkyl side-chain lengths. The nonbonded EF-CG forces for the ionic liquid with a short side chain were extended to generate the nonbonded forces for the ionic liquids with longer side chains. The EF-CG force fields for the ionic liquids exhibit very good transferability between different systems at various temperatures and are suitable for investigating the mesoscopic structural properties of this class of ionic liquids. The good additivity and ease of manipulation of the EF-CG force fields can allow for an inverse design methodology of ionic liquids at the coarse-grained level. With the EF-CG force field, the molecular dynamics (MD) simulation at a very large scale has been performed to check the significance of finite size effects on the structural properties. From these MD simulation results, it can be concluded that the finite size effect on the phenomenon of ionic liquid spatial heterogeneity (Wang, Y.; Voth, G. A. J. Am. Chem. Soc. 2005, 127, 12192) is small and that this phenomenon is indeed a nanostructural behavior which leads to the experimentally observed mesoscopic heterogeneous structure of ionic liquids.

The effects of polymer morphology on proton solvation and transport in hydrated Nafion are investigated by using a novel reactive molecular dynamics approach. Three of the most significant morphological models of Nafion, the lamellar model, the cylinder model, and the cluster-channel model, are studied. The three models exhibit distinct proton transport (PT) patterns, which result in different proton diffusion rates. In both the lamellar and the cylinder models, the interaction between protons and the sulfonate groups is shown to be the key factor in determining PT behavior. For the cluster-channel model, the geometrical shape also plays an important role in influencing the PT behavior. The change in the excess proton solvation structure as a function of the distance between protons and sulfonate groups is also analyzed. It is found that the increase of the water cylinder radius or water layer height leads to the presence of more protons around the sulfonate groups, while, for the cluster model, an increase in the water sphere radius leads to the presence of fewer protons around the sulfonate groups. Furthermore, for the lamellar and cylinder models, the hydrated protons around the sulfonate groups consist of more Zundel-like (H 5 O 2 + ) structures when the hydration levels decrease, which is also influenced by the different morphological structures of Nafion.