89 research outputs found
Assessment of Hydration Thermodynamics at Protein Interfaces with Grid Cell Theory
Molecular
dynamics simulations have been analyzed with the Grid
Cell Theory (GCT) method to spatially resolve the binding enthalpies
and entropies of water molecules at the interface of 17 structurally
diverse proteins. Correlations between computed energetics and structural
descriptors have been sought to facilitate the development of simple
models of protein hydration. Little correlation was found between
GCT-computed binding enthalpies and continuum electrostatics calculations.
A simple count of contacts with functional groups in charged amino
acids correlates well with enhanced water stabilization, but the stability
of water near hydrophobic and polar residues depends markedly on its
coordination environment. The positions of X-ray-resolved water molecules
correlate with computed high-density hydration sites, but many unresolved
waters are significantly stabilized at the protein surfaces. A defining
characteristic of ligand-binding pockets compared to nonbinding pockets
was a greater solvent-accessible volume, but average water thermodynamic
properties were not distinctive from other interfacial regions. Interfacial
water molecules are frequently stabilized by enthalpy and destabilized
entropy with respect to bulk, but counter-examples occasionally occur.
Overall detailed inspection of the local coordinating environment
appears necessary to gauge the thermodynamic stability of water in
protein structures
Relationship between Structure, Entropy and Diffusivity in Water and Water-like Liquids
Anomalous behaviour of the excess entropy () and the associated scaling
relationship with diffusivity are compared in liquids with very different
underlying interactions but similar water-like anomalies: water (SPC/E and
TIP3P models), tetrahedral ionic melts (SiO and BeF) and a fluid with
core-softened, two-scale ramp (2SRP) interactions. We demonstrate the presence
of an excess entropy anomaly in the two water models. Using length and energy
scales appropriate for onset of anomalous behaviour, the density range of the
excess entropy anomaly is shown to be much narrower in water than in ionic
melts or the 2SRP fluid. While the reduced diffusivities () conform to the
excess entropy scaling relation, for all the systems
(Y. Rosenfeld, Phys. Rev. A {\bf 1977}, {\it 15}, 2545), the exponential
scaling parameter, , shows a small isochore-dependence in the case of
water. Replacing by pair correlation-based approximants accentuates the
isochore-dependence of the diffusivity scaling. Isochores with similar
diffusivity scaling parameters are shown to have the temperature dependence of
the corresponding entropic contribution. The relationship between diffusivity,
excess entropy and pair correlation approximants to the excess entropy are very
similar in all the tetrahedral liquids.Comment: 24 pages, 4 figures, to be published in Journal of Physical Chemistry
Rapid and Accurate Prediction and Scoring of Water Molecules in Protein Binding Sites
Water plays a critical role in ligand-protein interactions. However, it is still challenging to predict accurately not only where water molecules prefer to bind, but also which of those water molecules might be displaceable. The latter is often seen as a route to optimizing affinity of potential drug candidates. Using a protocol we call WaterDock, we show that the freely available AutoDock Vina tool can be used to predict accurately the binding sites of water molecules. WaterDock was validated using data from X-ray crystallography, neutron diffraction and molecular dynamics simulations and correctly predicted 97% of the water molecules in the test set. In addition, we combined data-mining, heuristic and machine learning techniques to develop probabilistic water molecule classifiers. When applied to WaterDock predictions in the Astex Diverse Set of protein ligand complexes, we could identify whether a water molecule was conserved or displaced to an accuracy of 75%. A second model predicted whether water molecules were displaced by polar groups or by non-polar groups to an accuracy of 80%. These results should prove useful for anyone wishing to undertake rational design of new compounds where the displacement of water molecules is being considered as a route to improved affinity
An evaluation review of the prediction of protonation states in proteins versus crystallographic experiment
From model complexes to metalloprotein inhibition: A synergistic approach to structure-based drug discovery
Comparison of Free-Energy Methods to Calculate the Barriers for the Nucleophilic Substitution of Alkyl Halides by Hydroxide
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