PME Switching in Confinement Simulations of Charged Solutes.

The confinement method is a reaction coordinate-free enhanced sampling method for the calculation of conformational free energy differences. We show that in explicit solvent, artifacts occur when treating charged solutes. These artifacts are resolved by switching off the particle mesh Ewald (PME) method at the start of confinement.

Conformational Free-Energy Differences of Large Solvated Systems with the Focused Confinement Method.

The focused confinement method (FCM) is a reaction coordinate-free simulation approach for the calculation of conformational free-energy differences in explicit solvent. The method uses reference states for the conformations of interest, partitions the solute into conformationally active and inactive regions, and requires the calculation of desolvation free energies of mixed harmonic-anharmonic states as part of its procedure. The reference states and partitioning affect the speed of convergence of FCM's constituent simulations in opposing manners, but in the thermodynamic limit, they have no effect on calculated conformational free-energy differences.

Calculation of Conformational Free Energies with the Focused Confinement Method.

We introduce the focused confinement method, a reaction coordinate-free simulation approach for the calculation of conformational free energies. These are obtained in a series of restrained simulations that transform part of the molecule of interest to independent harmonic oscillators resulting in mixed harmonic-anharmonic states. It is shown that the free energy difference between these mixed states can be readily calculated through the construction of chimeric trajectories.