Table 1.

Absolute binding free energies of BACE1 and CatD^a

ΔG (kcal/mol)	BACE1	CatD
$\mathrm{\Delta }{G}_{\text{dsolv}}^{\mathrm{L}}$	47.5±0.3	47.5±0.3
$\mathrm{\Delta }{G}_{\text{res}}^{\mathrm{L}}$	16.4	15.5
$\mathrm{\Delta }{G}_{\text{coup}}^{\mathrm{C}}$	−73.7±0.2	−70.0±0.3
$\mathrm{\Delta }{G}_{\text{res}}^{\mathrm{C}}$	−3.7±0.1	−6.7±0.3
ΔGfinite–size	1.3	1.4
ΔG(pHref)	−12.1±0.4	−12.2±0.5
ΔG(pH 4.6)	−13.8±0.4	−12.5±0.5

^aΔG(ref) refers to that calculated using the fixed-protonation- state free energy calculations. Individual free energy contributions are explained in the main text. ΔG_{finite–size} represents the correction to the electrostatic energy calculated with particle mesh Ewald under periodic boundary conditions for charged systems.²² No error bars are given for $\mathrm{\Delta }{G}_{\text{res}}^{\mathrm{L}}$ and ΔG_{finite–size}, as they were calculated analytically. The error bar of ΔG(pH 4.6) was estimated by combining the errors in ΔG(pH^ref) and the pH-dependent corrections. As to the latter, the free energy errors due to titration of His45 (0.24) and His145 (0.09) were used for BACE1, and the inhibitor titratable site (0.16) was used for CatD.