Table 3.

Free energies of perturbed charges binding to the wild-type (WT), single V82A mutant (1X), and the I63P/V82T/I84V triple mutant (3X). All atoms of the template inhibitors are fixed at their initial values other than the charges noted. The column labeled “Analog” represents the chemical functional group that is being modeled by the perturbation. Specificity values (ΔSp) are computed as the change in electrostatic binding free energy from the starting charges to the worst-of-best target (see Methods).

Atoms	Analog	$\Delta \Delta G_{\mathit{es}}^{\mathit{WT}}$	$\Delta \Delta G_{\mathit{es}}^{1X}$	$\Delta \Delta G_{\mathit{es}}^{3X}$	Δ Sp
Amprenavir
C5=0.32 H5=−0.20	H→F	−0.89	−0.67	−0.74	0.67
C13=0.27 H13=−0.25	H→F	−0.25	−0.34	−0.25	0.25
C11=0.24 H11=−0.30	H→F	−0.47	−0.48	−0.23	0.23
C21=0.20 H21=−0.23	H→F	−0.28	−0.29	−0.23	0.23
C6=0.40 H6=−0.20	H→F	0.26	−0.20	−0.31	0.20
Indinavir
H34=−0.91	$\mathrm{H}\to {\mathrm{CO}}_2^{-}$	−3.91	−2.02	−2.79	2.02
C12=0.27 H12B=−0.25	H→F	−0.89	−0.68	−0.51	0.51
C18=0.25 H18=−0.25	H→F	−0.31	−0.38	−0.34	0.34
N2=0.00 H2=0.00	NH→CH2	−0.52	−0.32	−0.24	0.24
C19=0.23 H19=−0.25	H→F	−0.06	−0.23	−0.31	0.23
C34=0.45 H34=−0.11	H→F	−0.21	−0.29	−0.23	0.23
C35=0.43 H35=−0.12	H→F	−0.34	−0.20	−0.24	0.20
Nelfinavir
H9A=−0.92	$\mathrm{H}\to {\mathrm{CO}}_2^{-}$	−1.14	2.01	0.83	0.83
C20=0.35 H20=−0.15	H→F	−0.58	−1.17	−0.90	0.90
N12=0.00 HN12=0.00	NH→CH2	−0.73	−0.87	−0.95	0.87
O38=−0.08 HO38=−0.08	NH2→CH3	−1.74	−0.68	−0.47	0.47
C80=0.30 H80=−0.25	H→F	−0.31	−0.26	−0.32	0.26
C9=0.20 H9A=−0.22	H→F	−0.13	−0.28	−0.22	0.22
Ritonavir
H86A=−0.97	$\mathrm{H}\to {\mathrm{CO}}_2^{-}$	−3.39	−2.34	−3.12	2.34
H90B=−0.95	$\mathrm{H}\to {\mathrm{CO}}_2^{-}$	−3.98	−3.10	−2.28	2.28
C12=0.41 H12=−0.20	H→F	−0.81	−0.88	−0.93	0.88
C15=0.40 H15=−0.20	H→F	−1.19	−0.64	−0.71	0.64
N5=−0.05 C1=−0.05 C4=−0.05	N→CH	−1.16	−0.82	−0.54	0.54
C75=0.28 H75B=−0.25	H→F	−0.12	−0.34	−0.31	0.31
C4=0.54 H4=−0.20	H→F	−0.05	−0.31	−0.20	0.20
C33=0.26 H33=−0.25	H→F	−0.18	−0.21	−0.29	0.21
Saquinavir
H6=−0.85	$\mathrm{H}\to {\mathrm{CO}}_2^{-}$	−3.83	−3.91	−2.44	2.44
H7=−0.85	$\mathrm{H}\to {\mathrm{CO}}_2^{-}$	−3.59	−3.31	−2.16	2.16
H4=−0.83	$\mathrm{H}\to {\mathrm{CO}}_2^{-}$	−2.38	−1.93	−1.46	1.46
C16=0.30 H16=−0.25	H→F	−0.50	−0.70	−0.59	0.59
N1=0.00 C2=0.06 C10=0.06	N→CH	−0.29	−0.31	−0.35	0.31
C27=0.20 H27A=−0.25	H→F	0.10	−0.28	−0.22	0.22
C8=0.22 H8=−0.20	H→F	−0.10	−0.21	−0.25	0.21
C4=0.20 H4=−0.26	H→F	0.01	−0.17	−0.31	0.17
C30=0.20 H30A=−0.20	H→F	−0.16	−0.15	−0.23	0.15
N3=−0.10 HN3A=0.00 HN3B=0.00	NH2→CH3	−0.73	−0.42	0.02	−0.02
H8=−0.88	$\mathrm{H}\to {\mathrm{CO}}_2^{-}$	−1.04	−0.80	1.66	−1.66
Tipranavir
H37=−0.84	$\mathrm{H}\to {\mathrm{CO}}_2^{-}$	−1.68	−1.03	−1.21	1.03
N28=−0.20 HN28=0.00	NH→CH2	−1.45	−1.07	−1.03	1.03
C38=0.26 H38=−0.20	H→F	−0.09	−0.25	−0.30	0.25
F42=−1.15	$\mathrm{H}\to {\mathrm{CO}}_2^{-}$	−1.32	−2.30	−0.24	0.24
C39=0.15 F40=0.10	F→H	−0.54	−0.41	−0.22	0.22
C37=0.28 H37=−0.20	H→F	−0.04	−0.19	−0.27	0.19
C17=0.28 H17=−0.25	H→F	−0.12	−0.17	−0.13	0.13