Table 1.
Experimental and calculated pKa’s of the catalytic residues in BACE1/BACE2/CatD, HEWL and SNasea
| Expt | PropKa | APBS | Hybr | All-atom | |
|---|---|---|---|---|---|
| BACE1 | |||||
| Asp32 | 5.2 | 8.0/4.4 | 5.5/5.4 | 4.1/4.2 | 3.7/4.1 |
| Asp228 | 3.5 | 4.3/7.9 | 5.2/5.1 | 1.9/1.8 | −0.4/−0.6 |
| BACE2 | |||||
| Asp48 | n/d | 6.9/5.2 | 6.3/5.6 | 3.5/3.7 | n/d |
| Asp241 | n/d | 5.2/6.9 | 6.2/5.7 | 2.2/1.9 | n/d |
| CatD | |||||
| Asp33 | >5 | 8.4/4.6 | 10.5/6.2 | 4.4/4.7 | n/d |
| Asp231 | 4.1 | 3.1/8.3 | 11.9/6.6 | 3.2/2.9 | n/d |
| HEWL | |||||
| Glu35 | 6.1 | 6.5 | 4.9/3.5 | 5.9/5.9 | 7.7/7.8 |
| Asp52 | 3.6 | 3.9 | −0.3/2.3 | 3.7/3.7 | 5.7/5.6 |
| SNase | |||||
| Asp19 | 2.2 | 4.2/2.9 | 7.5/5.0 | 1.6/1.5 | 3.5/3.3 |
| Asp21 | 6.5 | 2.3/3.7 | 7.1/4.7 | 4.3/4.4 | 5.8/6.0 |
The nucleophile (lower experimental pKa or by homology to BACE1) is highlighted in italics. The experimental pKa’s of HEWL and SNase are taken from NMR data,31,33 while those of BACE1 and CatD are inferred from kinetic experiments.29,34 The same structures with missing residues added were used in all calculations. The empirical calculations (PropKa 3.111,12 ) returned two sets of pKa’s for the coupled dyads in BACE1/BACE2/CatD and SNase. For the APBS calculations (version 1.4.115,16), two pKa’s are listed corresponding to the use of an effective protein dielectric constant of 4 or 20. The van der Waals surface based on the CHARMM radii was used. For the CpHMD simulations, the first pKa corresponds to the microscopic residue-specific pKa, while the second one corresponds to the macroscopic stepwise pKa. The hybrid-solvent CpHMD data for BACE1 and CatD were taken from our previous work.26,35