Free Energy Computation for an Isomerizing Chromophore in a Molecular Cavity via the Average Solvent Electrostatic Configuration Model: Applications in Rhodopsin and Rhodopsin-Mimicking Systems.

We present a novel technique for computing the free energy differences between two chromophore "isomers" hosted in a molecular environment (a generalized solvent). Such an environment may range from a relatively rigid protein cavity to a flexible solvent environment. The technique is characterized by the application of the previously reported "average electrostatic solvent configuration" method, and it is based on the idea of using the free energy perturbation theory along with a chromophore annihilation procedure in thermodynamic cycle calculations. The method is benchmarked by computing the ground-state room-temperature relative stabilities between (i) the