Table 1.

Free energy values of each of thermodynamic terms in double decoupling method (method 1).

Guest	$\mathbf{\Delta }{\mathbf{G}}_{\mathbf{rest}–\mathbf{on}}^{\mathit{C}}$	$\mathbf{\Delta }{\mathit{G}}_{\mathbf{elec–off}}^{\mathit{C}}$	$\mathbf{\Delta }{\mathit{G}}_{\mathbf{vdw}–\mathbf{off}}^{\mathit{C}}$	$\mathbf{\Delta }{\mathbf{G}}_{\mathbf{rest-off}}^{\mathit{C}}$	$\mathbf{\Delta }{\mathbf{G}}_{\mathbf{elec–off}}^{\mathit{G}}$	$\mathbf{\Delta }{\mathit{G}}_{\mathbf{vdw}–\mathbf{off}}^{\mathit{G}}$	ΔPΔV	ΔGbind	ΔGexpt
G0	0.83 ± 0.06	−23.75 ± 0.03	−10.02 ± 0.95	−1.66 ± 0.02	−26.56 ± 0.03	−40.73 ± 0.05	24.63	−8.05 ± 0.88	−6.69 ± 0.05
G1	0.10 ± 0.04	24.24 ± 0.15	−47.94 ± 1.31	−1.83 ± 0.03	19.43 ± 0.20	−67.54 ± 0.03	21.25	−1.43 ± 1.51	−7.65 ± 0.04
G2	0.84 ± 0.05	−2.96 ± 0.06	−19.81 ± 0.20	−1.50 ± 0.01	−6.67 ± 0.01	−48.80 ± 0.07	21.79	−10.25 ± 0.20	−7.66 ± 0.05
G3	0.37 ± 0.06	−18.83 ± 0.04	−44.21 ± 0.99	−1.49 ± 0.01	−22.34 ± 0.05	−76.03 ± 0.16	23.39	−10.82 ± 0.85	−6.45 ± 0.06
G4	2.01 ± 0.13	−56.13 ± 0.19	−38.10 ± 0.11	−1.46 ± 0.00	−60.58 ± 0.08	−78.37 ± 0.56	39.85	−5.42 ± 0.51	−7.80 ± 0.04
G5	1.03 ± 0.08	26.31 ± 0.05	4.98 ± 0.11	−0.43 ± 0.01	25.59 ± 0.08	−22.59 ± 0.08	12.60	−16.29 ± 0.34	−8.18 ± 0.05
G6	2.10 ± 0.05	46.88 ± 0.19	8.86 ± 0.08	−1.52 ± 0.02	47.25 ± 0.06	−11.84 ± 0.01	9.18	−11.73 ± 0.23	−8.34 ± 0.05
G7	1.11 ± 0.02	45.69 ± 0.07	10.38 ± 0.07	−0.82 ± 0.01	46.81 ± 0.03	−13.50 ± 0.08	9.71	−13.34 ± 0.14	−10.00 ± 0.10
G8	1.16 ± 0.40	36.29 ± 0.07	8.21 ± 0.33	−1.97 ± 0.02	32.23 ± 0.03	−22.74 ± 0.01	14.54	−19.67 ± 0.30	−13.50 ± 0.04
G9	1.50 ± 0.05	101.92 ± 0.18	11.74 ± 0.12	−1.37 ± 0.00	100.09 ± 0.04	−9.79 ± 0.05	9.63	−13.87 ± 0.13	−8.68 ± 0.08
G10	1.83 ± 0.07	122.60 ± 0.04	15.10 ± 0.30	−1.44 ± 0.00	126.17 ± 0.03	−11.27 ± 0.13	11.43	−11.76 ± 0.20	−8.22 ± 0.07
G11	3.10 ± 0.06	104.23 ± 0.16	9.23 ± 0.06	−1.48 ± 0.01	106.86 ± 0.06	−9.74 ± 0.08	10.26	−7.70 ± 0.21	−7.77 ± 0.05
G11*	2.17 ± 1.04	94.91 ± 0.59	−4.18 ± 0.61	−1.60 ± 0.02	106.86 ± 0.06	−9.74 ± 0.08	9.71	15.54 ± 2.21	N/A
G12	8.22 ± 1.13	−23.63 ± 0.08	−29.05 ± 0.66	−1.50 ± 0.00	−27.94 ± 0.03	−58.74 ± 1.60	26.83	− 13.90 ± 2.40	− 9.86 ± 0.03
G13	0.77 ± 0.08	226.92 ± 0.16	6.04 ± 0.11	−1.87 ± 0.02	225.54 ± 0.04	−12.55 ± 0.15	14.09	−4.79 ± 0.36	−7.11 ± 0.03
G13*	2.32 ± 0.24	232.26 ± 0.31	−1.68 ± 0.14	−1.77 ± 0.00	225.54 ± 0.04	−12.55 ± 0.15	14.00	−4.11 ± 0.27	N/A

ΔG_bind and ΔG_expt are the computed and experimental binding free energies, respectively. ΔG_{rest –on} and ΔG_{rest –off} are the free energy changes due to applying and releasing the restraint and ΔG_{elec –off} and ΔG_vdw–off denote the contributions of electrostatic and vdW interactions, respectively. Superscript ‘C’ and ‘G’ respectively denote the host-guest complex and guest-only. ΔPΔV denotes the work associated with differences in pressure and volume between the alchemical pathways of the host-guest complex and guest-only. All standard errors for ΔPΔV are less than 10⁻² kcal/mol. Means and standard errors are obtained from three independent simulations using different randomly assigned initial velocities.

^*Represents values for the second guest molecule.