Exploring Routes to Enhance the Calculation of Free Energy Differences via Nonequilibrium Work SQM/MM Switching Simulations by Using Hybrid Charge Intermediates Between MM and SQM Level of Theory or Non-linear Switching Schemes

Nonequilibrium work switching simulations and Jarzynskis equation are a reliable method to compute free energy differences, Alowhigh, between two levels of theory, such as a pure molecular mechanical (MM) and a quantum mechanical/molecular mechanical (QM/MM) description of a system of interest. Despite the inherent parallelism, the computational cost of this approach can quickly get very high. This is particularly true for systems where the core region, the part of the system to be described at different levels of theory, is embedded in an environment, such as explicit solvent water. We find that even for relatively simple solutewater systems, switching lengths of at least 5 ps are necessary to compute Alowhigh reliably. In this study, we investigate two approaches towards an affordable protocol, with emphasis on keeping the switching length well below 5 ps. Inserting a hybrid charge intermediate state with modified partial charges which resembles the charge distribution of the desired high level makes it possible to obtain reliable calculations with 2 ps switches. Attempts using step-wise linear switching paths, on the other hand, did not lead to improvement, i.e., faster convergence for all systems. To understand these findings, we analyzed the solutes properties as a function of partial charges used, the number of waters in direct contact with the solute, and studied the time needed for water molecules to reorient themselves upon a change in the solutes charge distribution.