Quantitative models of biomolecular hydration thermodynamics

This thesis explores the use of cell theory calculations to characterise hydration thermodynamics in small molecules (cations, ions, hydrophobic molecules), proteins and protein-ligand complexes. Cell theory uses the average energies, forces and torques of a water molecule measured in its molecular frame of reference to parameterise a harmonic potential. From this harmonic potential analytical expressions for entropies and enthalpies are derived. In order to spatially resolve these thermodynamic quantities grid points are used to store the forces, torques, and energies of nearby waters which giving rise to the new grid cell theory (GCT) model. GCT allows one to monitor hydration thermodynamics at heterogeneous environments such as that of a protein surface. Through an understanding of the hydration thermodynamics around the protein and particularly around binding sites, robust protein-ligand scoring functions are created to estimate and rank protein-ligand binding affinities. GCT was then able to retrospectively rationalise the structure activity relationships made during lead optimisation of various ligand-protein systems including Hsp90, FXa, scytalone dehydratase among others. As well as this it was also used to analyse water behaviour in various protein environments with a dataset of 17 proteins. The grid cell theory implementation provides a theoretical framework which can aid the iterative design of ligands during the drug discovery and lead optimisation processes, and can provide insight into the effect of protein environment to hydration thermodynamics in general

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