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. Author manuscript; available in PMC: 2022 May 6.
Published in final edited form as: J Phys Chem B. 2021 Apr 27;125(17):4241–4261. doi: 10.1021/acs.jpcb.0c10263

Figure 1.

Figure 1.

Protocols for the equilibrium (EQ) and nonequilibrium (NEQ) free energy calculations. (a) EQ sampling scheme. A separate molecular dynamics (MD) simulation (colored arrows) is performed for each of a set of discrete λ windows corresponding to different states of the system (λ1−λN). (b) NEQ approach, where two equilibrium simulations at the physical end states are run (λ1 and λN, blue and pink arrow). The alchemical path is explored in fast switching transitions in a single simulation (grey arrows). In the bidirectional approach, many trials are performed in both directions and the non-equilibrium work distributions of the forward and reverse direction (P(W) and P(−W)) are directly related to the free energy difference between the states (thick horizontal line between the distributions) by the Crooks fluctuation theorem. Figure was adapted from Mey et al.14 under the CC-BY 4.0 license.