Table I.

Computed free energies of transfer from binding pocket to vacuum for phenol. All free energies are listed in kcal/mol. Uncertainties listed represent one standard deviation of the mean, estimated by the block bootstrap procedure described in Sec. III I. The different orientations are explained in the text, and denote the ligand initial orientation as well as the orientation to which the ligand was restrained. For the orientational restraint calculations, listed times indicate the simulation length at each lambda value in the restraining portion of the calculation. The 1 and 5 ns calculations for this portion were separate sets of simulations. All the other portions employed simulations 1 ns in length for each lambda value, except the vacuum calculation, which was 5 ns in length. For the calculations with no orientational restraints, times denote the time spent on each portion of the calculation. The values reported here are explained in Sec. III L. ΔG_tans values shown in bold are those we believe to be converged (within statistical uncertainty of the best estimate).

	$\mathrm{\Delta }{G}_{\text{restr}}^{PL}$	$\mathrm{\Delta }{G}_{\text{elec}}^{PL}$	$\mathrm{\Delta }{G}_{\text{LJ}}^{PL}$	$\mathrm{\Delta }{G}_{\text{restr}}^{{\text{H}}_2\text{O}}$	ΔGsym	$\mathrm{\Delta }{G}_{\text{elec}}^{\text{vac}}$	ΔGtans
Standard approach
Orientation 1
1 ns	0.65±0.01	18.95±0.05	9.37±0.04	−6.58	0.41	−12.82±0.01	9.98±0.06
Orientation 2
1 ns	2.90±0.12	16.34±0.03	8.44±0.06	−6.73	0.41	−12.82±0.01	8.54±0.14
5 ns	4.31±0.16						9.95±0.18
Orientation decomposition
Orientation 1
1 ns	0.65±0.01	19.00±0.02	9.37±0.04	−6.58	0.41	−12.82±0.01	10.03 ±0.05
Orientation 2
1 ns	0.34±0.01	16.32±0.03	8.44±0.07	−6.73	0.41	−12.82±0.01	5.96±0.07
Combined
1 ns							10.03±0.05
No orientatinal restraints
1 ns	0.28±0.01	18.98±0.04	4.36±0.08	−5.26	0.41	−12.82±0.01	5.95±0.09
5 ns	0.28±0.01	18.85±0.02	3.93±0.07			−12.82±0.01	5.39±0.09