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. By focusing the confinement to the conformationally active region, the method requires fewer restrained simulations than the traditional confinement method, which eases the treatment of large systems. The accuracy and efficiency of the method is demonstrated for implicitly and explicitly solvated systems.