. Author manuscript; available in PMC: 2022 Nov 26.

Published in final edited form as: J Chem Theory Comput. 2022 Mar 7;18(4):2114–2123. doi: 10.1021/acs.jctc.1c00948

Table 2:

Free Energy Estimator Accuracy Relative to Reference Calculation

	c = 15.5			c = 5.5
	1 kcal/mol barrier			No barrier
Estimator^a	cRMSE	MUE	R	cRMSE	MUE	R
	T4L 3 Site System
Independent site	0.41	0.73	0.972	0.43	0.94	0.971
Potts model	0.22	0.38	0.994	0.07	0.07	0.999
Histogram-based	0.23	0.36	0.994	0.07	0.08	0.999
	T4L 4 Site System
Independent site	0.53	0.59	0.923	0.70	0.64	0.896
Potts model	0.48	0.41	0.922	0.44	0.43	0.948
Histogram-based	0.51	0.41	0.922	0.46	0.51	0.940
	T4L 5 Site System
Independent site	0.68	0.88	0.892	0.92	1.44	0.789
Potts model	0.59	0.46	0.924	0.55	0.57	0.933
Histogram-based	-	-	-	-	-	-
	HIV-RT Inhibitors
Independent site	0.48	0.97	0.974	0.50	1.02	0.973
Potts model	0.30	0.26	0.990	0.37	0.29	0.985
Histogram-based	0.31	0.25	0.989	-	-	-
	p38 Inhibitors
Independent site	0.36	0.87	0.958	0.45	0.90	0.945
Potts model	0.42	0.59	0.952	0.52	0.61	0.935
Histogram-based	0.46	0.54	0.942	-	-	-

The best estimator for each system and metric is highlighted in bold. If insufficient sampling is available to estimate free energies for all alchemical states with a particular estimator, a dash is displayed.