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. Author manuscript; available in PMC: 2019 May 2.
Published in final edited form as: J Chem Theory Comput. 2016 Mar 23;12(4):1466–1480. doi: 10.1021/acs.jctc.5b01188

Figure 6:

Figure 6:

The free energy difference estimate with NBB-direct is dependent on the thermodynamic path connecting the unsampled states. Higher order mixing rules for the unsampled QM/MM intermediate states lead to statistically significant biases in the estimate. The dashed line indicates the free energy estimate using the full MBAR method.