Evaluation of water displacement energetics in protein binding sites with grid cell theory

Abstract

Excess free energies, enthalpies and entropies of water in protein binding sites were computed via classical simulations and Grid Cell Theory (GCT) analyses for three pairs of congeneric ligands in complex with the proteins scytalone dehydratase, p38α MAP kinase and EGFR kinase respectively. Comparative analysis is of interest since the binding modes for each ligand pair differ in the displacement of one binding site water molecule, but significant variations in relative binding affinities are observed. Protocols that vary in their use of restraints on protein and ligand atoms were compared to determine the influence of protein-ligand flexibility on computed water structure and energetics, and to assess protocols for routine analyses of protein-ligand complexes. The GCT-derived binding affinities correctly reproduce experimental trends, but the magnitude of the predicted changes in binding affinities is exaggerated with respect to results from a previous Monte Carlo Free Energy Perturbation study. Breakdown of the GCT water free energies into enthalpic and entropic components indicates that enthalpy changes dominate the observed variations in energetics. In EGFR kinase GCT analyses revealed that replacement of a pyrimidine by a cyanopyridine perturbs water energetics up three hydration shells away from the ligand.

Thermodynamic Insight into the Effects of Water Displacement and Rearrangement upon Ligand Modifications using Molecular Dynamics Simulations

“…Gerogiokas et al. used the same inhibitor pair to evaluate the water displacement energetics using grid cell theory . With their approach, they obtained a ΔΔ G solv (PA→PB) value of 4.4 kcal mol −1 , which is in very close agreement with our value of 4.74 kcal mol −1 .…”

“…This effect counteracts the desolvation costs associated with the displacement of HS1. For the sake of simplicity, we term the two inhibitors as A and B in the following and use a similar notation as in a previous study with related content . ΔΔ G solv (AP→BP) corresponds to the difference in protein–ligand complex solvation free energy for the two ligands.…”

“…This approach accounts for reorganization of the solvent. Previous studies used a similar approach employing grid cell theory or 3D‐RISM to account for the solvent perturbation upon ligand scaffold modifications . Changes in solvation energies can be used not only to rationalize differences in binding energies of chemically different ligands, but also for binding pose flips, as shown recently …”

“…Previous studies used as imilar approach employing grid cell theory or 3D-RISM to account for the solvent perturbation upon ligand scaffold modifications. [18,19] Changes in solvation energies can be used not only to rationalize differences in binding energies of chemically differentl igands,b ut also for binding pose flips,ass hown recently. [20] In the present study,w eu sed hydration site analysis( HSA) based on inhomogeneousf luid solvation theory (IFST) [21,22] to estimate binding site solvation free energies for congeneric ligand pairs at several receptors (Table 1).…”

Elucidation of Nonadditive Effects in Protein–Ligand Binding Energies: Thrombin as a Case Study

“…18 The analysis presented in Figure 10 could have been extended to other components of the potential energy function, for instance changes in hydration enthalpies have been proposed to contribute to non-additivity in some protein-ligand complexes, 55 and these could be computed using molecular simulation trajectory analyses methodologies. [56][57][58] However, exploratory calculations suggest that converging hydration energy components to a level of precision sufficient to enable meaningful comparison between ligands will require significantly longer simulations than what was achieved here. Nevertheless it is now clear from the data depicted in Figure 10B that a profound understanding of non-additive effects in this system requires consideration of interactions occurring across the entire thrombin binding site.…”