Table 1. pKa values calculated for geometries of complexes of the bound inhibitor 18 [2-(1-naphtyl)ethyl derivative] in dGMII and JBMan enzymes (four different ionized combinations of the inhibitor and the amino acid Asp341-dGMII or Asp268-JBMan were included) optimized at the QM/MM level.
The preferred pyrrolidine ring conformation of the bound inhibitor and selected geometry parameters (interatomic distances between selected atoms (N1 and C5) of the inhibitor and (Zn2+ ion and Asp204) of the enzymes are also compiled.
| neutral/ionized form | Conformat ion of the ring | Interatomic distances(in Å) | pKa values and preferred ionized form | |||||
|---|---|---|---|---|---|---|---|---|
| dGMII | d(N1-Zn2+) | d(N1-O-asp204) | d(C5-O-asp204) | N1-inhibitor | Asp34l | Asp340 | Asp270 | |
| empty active site (PDB ID: 3BUB) | 5.8 (Asp-) | 4.3 (Asp-) | 1.2 (Asp-) | |||||
| swainsonine-dGMII (PDB ID: 3BLB) | E1 | 3.92 | 2.75 | 3.92 | 5.0 (N0-pyr) | 5.6 (Asp-) | 4.3 (Asp-) | 1.1 (Asp-) |
| swainsonine-dGMII (PDB ID: 1HWW) | 2 E | 4.11 | 2.88 | 3.90 | 5.3 (N0-pyr) | 5.6 (Asp-) | 3.1 (Asp-) | 6.3 (Ash0) |
| inh0-Asp341- | E 1 | 3.99 | 3.13 | 3.98 | 5.5 (N0-pyr) | 5.9 (Asp-) | 0.6 (Asp-) | 4.4 (Asp-) |
| 2E/E1 | 4.20 | 3.14 | 3.81 | 5.8 (N0-pyr) | 5.9 (Asp-) | 1.0 (Asp-) | 4.4 (Asp-) | |
| inh0-Ash3410 | E 1 | 4.13 | 3.18 | 3.83 | 5.5 (N0-pyr) | 6.0 (Ash0) | 0.1 (Asp-) | 4.6 (Asp-) |
| 2 E | 3.99 | 3.13 | 3.96 | 5.6 (N0-pyr) | 5.9 (Asp-) | 0.0 (Asp-) | 4.6 (Asp-) | |
| inh+-Asp341- | E1/2E | 3.99 | 2.74 | 3.91 | 5.1 (N0-pyr) | 6.0 (Ash0) | 1.3 (Asp-) | 4.5 (Asp-) |
| inh+-Ash3410 | E 1 | 3.95 | 2.72 | 3.94 | 5.3 (N0-pyr) | 5.7 (Asp-) | 1.0 (Asp-) | 4.3 (Asp-) |
| JBMan | N1-inhibitor | Asp268 | Asp267 | His209 | ||||
| empty active site (PDB ID: 6B9O) | 7.5 (Ash0) | -0.3 (Asp-) | 7.6 (Hip+) | |||||
| swainsonine0-JBMan | 2 E | 4.23 | 3.26 | 3.85 | 7.8 (N+-pyr) | 5.1 (Ash0) | -0.3 (Asp-) | 7.9 (Hip+) |
| swainsonine+-JBMan | 2 E | 4.09 | 2.81 | 3.86 | 8.1 (N+-pyr) | 2.7 (Asp-) | 0.1 (Asp-) | 8.9 (Hip+) |
| inh0-Asp268- | Ei | 4.23 | 3.28 | 4.01 | 7.9 (N+-pyr) | 3.5 (Ash-) | 1.5 (Asp-) | 7.8 (Hip+) |
| 2E/E1 | 4.27 | 3.30 | 3.99 | 7.9 (N+-pyr) | 5.1 (Ash0) | -0.2 (Asp-) | 7.9 (Hip+) | |
| inh0-Ash2680 | Ei | 4.21 | 3.21 | 4.04 | 8.0 (N+-pyr) | 3.7 (Asp-) | 1.5 (Asp-) | 7.6 (Hip+) |
| 2E/E3 | 4.40 | 3.42 | 3.95 | 7.5 (N+-pyr) | 5.0 (Asp0) | 1.5 (Asp-) | 7.5 (Hip+) | |
| inh+-Asp268- | E 1 | 4.06 | 2.85 | 4.07 | 8.2 (N+-pyr) | 3.3 (Asp-) | 1.5 (Asp-) | 7.9 (Hip+) |
| inh+-Ash2680 | Ei | 4.04 | 2.75 | 4.03 | 8.0 (N+-pyr) | 4.1 (Asp-) | 1.5 (Asp-) | 7.7 (Hip+) |