Multi-level free energy simulation with a staged transformation approach.

Combining multiple levels of theory in free energy simulations to balance computational accuracy and efficiency is a promising approach for studying processes in the condensed phase. While the basic idea has been proposed and explored for quite some time, it remains challenging to achieve convergence for such multi-level free energy simulations as it requires a favorable distribution overlap between different levels of theory. Previous efforts focused on improving the distribution overlap by either altering the low-level of theory for the specific system of interest or ignoring certain degrees of freedom. Here, we propose an alternative strategy that first identifies the degrees of freedom that lead to gaps in the distributions of different levels of theory and then treats them separately with either constraints or restraints or by introducing an intermediate model that better connects the low and high levels of theory. As a result, the conversion from the low level to the high level model is done in a staged fashion that ensures a favorable distribution overlap along the way. Free energy components associated with different steps are mostly evaluated explicitly, and thus, the final result can be meaningfully compared to the rigorous free energy difference between the two levels of theory with limited and well-defined approximations. The additional free energy component calculations involve simulations at the low level of theory and therefore do not incur high computational costs. The approach is illustrated with two simple but non-trivial solution examples, and factors that dictate the reliability of the result are discussed.