Strategies to Calculate Water Binding Free Energies in Protein–Ligand Complexes

Water molecules are commonplace in protein binding pockets, where they can typically form a complex between the protein and a ligand or become displaced upon ligand binding. As a result, it is often of great interest to establish both the binding free energy and location of such molecules. Several approaches to predicting the location and affinity of water molecules to proteins have been proposed and utilized in the literature, although it is often unclear which method should be used under what circumstances. We report here a comparison between three such methodologies, Just Add Water Molecules (JAWS), Grand Canonical Monte Carlo (GCMC), and double-decoupling, in the hope of understanding the advantages and limitations of each method when applied to enclosed binding sites. As a result, we have adapted the JAWS scoring procedure, allowing the binding free energies of strongly bound water molecules to be calculated to a high degree of accuracy, requiring significantly less computational effort than more rigorous approaches. The combination of JAWS and GCMC offers a route to a rapid scheme capable of both locating and scoring water molecules for rational drug design

Self-Assembly of Calcium Carbonate Nanoparticles in Water and Hydrophobic Solvents

The self-assembly of Ca²⁺ and CO₃^2– ions into nanoparticles in water and hydrophobic solvents is investigated using molecular dynamics (MD) computer simulation. A new three-stage particle assembly procedure is used which relaxes the structure of the nanoparticle toward a lower energy state. In hydrophobic solvent the bare particle is essentially spherical whereas in water it is ellipsoidally shaped. With surfactant stabilizer the nanoparticles typically exhibit nonspherical cores in model hydrophobic solvents. Binary surfactant systems exhibit synergistic effects where for example a salicylate-sulfonate combination forms a cage which promotes a compact core. Synergistic effects on the shape of the particle were also observed in a hydrophobic solvent for surfactant-stabilized systems with trace water as a third component. The simulations show that rather than being a rigid structure the carbonate core shape and stabilizing shell coverage are sensitive to solvent, surfactant, and small polar molecules which act as cosurfactants