Table 1.

Binding energetics for perturbed pepstatin charge distributions based on the narrow specificity-optimized charge distribution. The column heading “Analog” represents the particular functional group change the charge perturbation is modeling. Negative values for the change in binding free energy of each complex is favorable while for specificity a positive value is favorable. Specificity values ΔSp are calculated as the difference between the lowest-energy decoy (pepsin or cathepsin D) and the target (HIV-1 protease) relative to the initial pepstatin charge distribution and are in units of kcal/mol.

Atoms	Analog	$\Delta \Delta G_{\mathit{es}}^{\mathit{HIV}}$	$\Delta {\Delta }_{\mathit{es}}^{\mathit{pep}\sin }$	$\Delta \Delta G_{\mathit{es}}^{\mathit{cath}.D}$	Δ Sp
Stabilize target and destabilize decoys
C4=−0.25 H4(A,B,C)=−0.25	${\mathrm{CH}}_3\to {\mathrm{CO}}_2^{-}$	−2.24	4.85	12.94	7.08
N4= 0.00 HN4= 0.00	NH→CH2	−0.21	0.85	0.86	1.06
C22= 0.30 H22A=−0.30	H→F	−0.13	0.42	1.01	0.55
C22= 0.30 H22B=−0.30	H→F	0.52	0.51	0.63	−0.01
C28= 0.30 H28B=−0.30	H→F	−0.13	0.80	0.01	0.14
Stabilize target (preferentially) and decoys
C32= 0.55 O7=−0.55 HO7=0.00	COH→CO	−3.19	−0.12	−0.88	2.31
O7= 0.00 HO7=0.00	OH→CH3	−1.56	−0.08	−0.93	0.63
C16= 0.30 H16A=−0.30	H→F	−0.48	0.16	−0.25	0.23
Destabilize decoys (preferentially) and target
C9=−0.25 H9(A,B,C)=−0.25	${\mathrm{CH}}_3\to {\mathrm{CO}}_2^{-}$	4.79	24.16	19.01	14.21
C10=−0.25 H10(A,B,C)=−0.25	${\mathrm{CH}}_3\to {\mathrm{CO}}_2^{-}$	0.55	13.52	6.71	6.17
C19=−0.25 H19(A,B,C)=−0.25	${\mathrm{CH}}_3\to {\mathrm{CO}}_2^{-}$	10.54	18.78	20.33	8.24
C31=−0.25 H31(A,B,C)=−0.25	${\mathrm{CH}}_3\to {\mathrm{CO}}_2^{-}$	2.85	13.12	13.20	10.27
C11=0.30 H11=−0.3	H→F	0.48	1.50	2.02	1.04
N3=0.00 HN3=0.00	NH→CH2	0.02	0.91	1.46	0.89