Table 1.
Free energy of binding and the surface-matching coefficients for different compounds evaluated in this study
| % of ΔGb |
Surface matching |
|||||||
| Cpd* | ΔGb value (kcal/mol)† | Distal pocket‡ | Proximal pocket | G-loop | Interface | External cleft | SML§ | SMH§ |
| MIN | −29.3 ± 4.7 (−22.7)¶ | 40 | — | — | — | — | 0.81 (0.80)¶ | 0.75 (0.67) |
| TAU | −28.4 ± 4.1 (−18.1) | 61 | — | — | — | — | 0.78 (0.69) | 0.50 (0.79) |
| ERY | −43.5 ± 5.3 (−10.0) | 24 | — | — | — | — | 0.45 (0.42) | 0.60 (0.66) |
| ERYA | −54.4 ± 5.8 (−7.7) | — | 12 | 4 | — | 17 | 0.66 (0.71) | 0.50 (0.67) |
| NCF | −42.5 ± 3.9 (−18.9) | 41 | — | — | — | — | 0.62 (0.54) | 0.29 (0.27) |
| CHL | −23.3 ± 4.6 (−20.3) | 52 | — | — | — | — | 0.78 (0.50) | 0.59 (0.20) |
| ETH | −31.0 ± 2.1 (−31.2) | 41 | — | — | — | — | 0.90 (0.84) | 0.00 (0.67) |
| OXA | −23.2 ± 4.2 (−20.9) | 52 | — | — | — | — | 0.70 (0.74) | 0.33 (0.60) |
| CIN | −22.9 ± 5.0 (−22.4) | 43 | — | — | 14 | — | 0.69 (0.55) | 0.48 (0.10) |
| CEF | −34.6 ± 3.3 (−28.8) | 32 | — | — | — | — | 0.77 (0.68) | 0.89 (0.84) |
| CEFA | −28.1 ± 5.0 (−20.5) | — | — | 9 | — | 48 | 0.51 (0.38) | 0.33 (0.78) |
| NMP | −22.3 ± 2.4 (−21.8) | 20 | — | 6 | 3 | 3 | 0.77 (0.67) | 0.48 (0.10) |
| NMP′ | −20.4 ± 2.9 (−11.6) | — | 3 | 7 | — | 14 | 0.63 (0.77) | 0.61 (0.38) |
| PAβN | −30.1 ± 5.3 (−2.4) | 29 | — | — | — | — | 0.68 (0.58) | 0.62 (0.19) |
| GLC | −22.4 ± 3.7 (−22.2) | 24 | — | — | — | — | 0.00 (0.00) | 0.84 (0.97) |
| KAN | −32.6 ± 6.7 (18.0) | 29 | — | — | — | — | 0.00 (0.00) | 0.64 (0.82) |
The calculations for all compounds refer to the drugs bound to the distal pocket of the binding protomer, except ERYA and CEFA, which deal with the drugs bound to the proximal pocket of the access protomer. NMP and NMP′ represent two independent runs of NMP from the distal binding site.
The contribution of the configurational entropy of the solute has not been included (SI Materials and Methods). Concerning the contributions of different regions (defined in Fig. 1) to ΔGb, only those larger than 2% are listed.
Residues within the various regions are listed in Fig. 1.
Calculated on the conformation of the complex with the lower rmsd from the average extracted from the unbiased MD simulations. SML and SMH refer to the lipophilic and hydrophilic-surface matching coefficients. See SI Materials and Methods for further details.
Values in parentheses are those for starting poses. ΔGb was calculated after 1,000 steps of structural optimization with restraints on heavy atoms of both protein and the ligand, to avoid the artifacts of high positive values created by the differences in bond lengths, angles, etc. specified by the docking program and the AMBER force field.