An Alternative to Conventional λ-Intermediate States in Alchemical Free Energy Calculations: λ-Enveloping...

Alchemical free energy calculations typically rely on intermediate states to bridge between the relevant phase spaces of the two end states. These intermediate states are usually created by mixing the energies or parameters of the end states according to a coupling parameter λ. The choice of the procedure has a strong impact on the efficiency of the calculation, as it affects both the encountered energy barriers and the phase space overlap between the states. The present work builds on the connection between the minimum variance pathway (MVP) and enveloping distribution sampling (EDS). It is shown that both methods can be regarded as special cases of a common scheme referred to as λ-EDS, which can also reproduce the behavior of conventional λ-intermediate states. A particularly attractive feature of λ-EDS is its ability to emulate the use of soft core potentials (SCP) while avoiding the associated computational overhead when applying efficient free energy estimators such as the multistate Bennett's acceptance ratio (MBAR). The method is illustrated for both relative and absolute free energy calculations considering five benchmark systems. The first two systems (charge inversion and cavity creation in a dipolar solvent) demonstrate the use of λ-EDS as an alternative coupling scheme in the context of thermodynamic integration (TI). The three other systems (change of bond length, change of dihedral angles, and cavity creation in water) investigate the efficiency and optimal choice of parameters in the context of free energy perturbation (FEP) and Bennett's acceptance ratio (BAR). It is shown that λ-EDS allows larger steps along the alchemical pathway than conventional intermediate states.