Table 4.

Free energies (in kcal/mol) of chemically-modified inhibitors interacting with the 3-class target ensemble. All energies are calculated as differences from the initial inhibitor binding energy.

Chemical Change	$\Delta \Delta G_{\mathit{es}}^{\mathit{WT}}$		$\Delta \Delta G_{\mathit{es}}^{1X}$		$\Delta \Delta G_{\mathit{es}}^{3X}$		Δ Sp
	Δ Δ Ges	Δ Δ Gtot	Δ Δ Ges	Δ Δ Gtot	Δ Δ Ges	Δ Δ Gtot	Δ Δ Ges	Δ Δ Gtot
Amprenavir
H21→F	−1.03	−1.77	0.34	−0.39	0.18	−0.39	−0.34	0.39
H11→F	−0.93	−1.50	0.49	−0.31	−0.28	−0.60	−0.49	0.31
H5→F	−1.03	3.07	−0.71	1.47	−0.23	2.83	0.23	−3.07
Indinavir
H18→F	−1.14	−1.75	−0.41	−0.68	−0.31	−0.74	0.31	0.68
H35→F	−1.19	−1.74	−0.03	−0.58	−0.04	−0.65	0.03	0.58
H34→F	−0.97	−1.38	0.00	−0.23	0.01	−0.24	−0.01	0.23
N2→CH2	−0.41	−0.42	−0.58	−0.17	−0.59	−0.38	0.58	0.17
H12B→F	−0.51	1.41	−0.31	0.46	−0.23	1.12	0.23	−1.12
$\mathrm{H}34\to {\mathrm{CO}}_2^{-}$	2.95	8.14	3.56	8.63	2.38	7.10	−3.56	−8.63
Nelfinavir
H80→F	−1.86	−2.35	−1.10	−1.31	−0.77	−1.28	0.77	1.28
H9A→F	−1.49	−0.42	−0.97	0.22	−0.46	−0.87	0.46	−0.22
N12→CH2	−0.81	2.01	−1.03	1.84	−0.96	2.69	0.96	−2.69
$\mathrm{H}9\mathrm{A}\to {\mathrm{CO}}_2^{-}$	1.72	−0.62	5.71	4.66	5.57	2.44	−5.71	−4.66
Ritonavir
H4→F	−2.65	−1.74	−0.13	−0.69	−0.22	−0.72	0.13	0.69
H33→F	−1.30	−1.94	−0.11	−0.70	−0.13	−0.65	0.11	0.65
H12→F	−2.09	−3.19	−2.57	−0.62	−1.64	−0.40	1.64	0.40
H75B→F	−1.80	−1.38	−0.68	−0.49	−1.24	−0.31	0.68	0.31
N5→CH3	−1.42	0.41	−1.32	0.68	−1.39	0.83	1.32	−0.83
H15→F	−2.86	2.01	−1.06	0.99	0.01	0.87	−0.01	−1.01
$\mathrm{C}86\to {\mathrm{CO}}_2^{-}$	2.16	3.89	2.30	4.74	4.46	7.07	−4.46	−7.07
$\mathrm{C}90\to {\mathrm{CO}}_2^{-}$	1.13	3.60	3.22	3.35	8.76	7.75	−8.76	−7.75
Saquinavir
H27A→F	−1.44	−0.39	−0.60	−0.76	−0.16	−0.69	0.16	0.69
N3→CH3	−0.19	−0.58	−0.28	−0.61	−0.32	−0.77	0.28	0.61
H8→F	−1.84	−1.77	−0.09	−0.43	−0.06	−0.76	0.06	0.43
H30A→F	−1.65	−0.19	−0.25	−0.80	−0.16	−0.31	0.16	0.31
H4→F	−1.93	−1.38	−0.40	−0.27	−0.15	−0.38	0.15	0.27
H16→F	−1.64	1.72	−4.70	−0.58	−0.65	1.46	0.65	−1.72
N1→CH2	−0.74	2.31	−0.86	2.01	−1.03	2.63	0.86	−2.01
$\mathrm{C}8\to {\mathrm{CO}}_2^{-}$	3.32	3.41	4.56	5.13	5.75	4.61	−5.75	−5.13
$\mathrm{C}7\to {\mathrm{CO}}_2^{-}$	1.55	3.76	2.25	5.23	3.50	4.56	−3.50	−5.23
$\mathrm{C}6\to {\mathrm{CO}}_2^{-}$	1.15	6.40	2.44	6.47	3.22	5.78	−3.22	−6.32
$\mathrm{C}4\to {\mathrm{CO}}_2^{-}$	1.19	6.41	2.53	6.67	3.85	5.66	−3.85	−6.47
Tipranavir
H37→F	−1.06	−1.54	−0.44	−0.70	−0.50	−1.14	0.44	0.70
F40→H	−0.30	−0.94	0.04	−0.57	−0.17	−0.97	−0.04	0.57
H17→F	−0.54	−1.22	−0.19	−0.94	−0.10	−0.32	0.10	0.32
$\mathrm{C}37\to {\mathrm{CO}}_2^{-}$	1.16	−0.54	3.88	2.84	3.05	1.20	−3.88	−2.84
$\mathrm{F}42\to {\mathrm{CO}}_2^{-}$	0.84	3.34	3.31	3.96	2.04	3.11	−3.31	−3.96