Table 1.
The number of events and the binding free energies estimated by the MM-GB/SA method in 28 trajectories of 200 ns for each ligand.
| Active site | Site 2 | Site 3 | Site 4 | Site 5 | Others | |
|---|---|---|---|---|---|---|
| Darunavir | ||||||
| On/off | 7/5 | 4/0 | 1/0 | 5/2 | 8/7 | 14[9]/25 |
| ∆G ave | − 28.4 (4.2) | − 24.2 (4.2) | − 17.2 (2.0) | − 26.6 (6.9) | − 18.8 (3.6) | − 22.3 (5.2) |
| ∆G min | − 32.7 | − 32.6 | − 17.9 | − 38.6 | − 21.2 | − 30.3 |
| Indinavir | ||||||
| On/off | 13/4 | 2/0 | 6/6 | 10/5 | 2/2 | 15[5]/31 |
| ∆G ave | − 33.2 (7.5) | − 33.7 (6.6) | − 22.0 (5.7) | − 28.4 (5.9) | − 24.6* (6.6) | − 26.5 (5.8) |
| ∆G min | − 56.1 | − 42.8 | − 28.8 | − 43.5 | − 26.5 | − 41.1 |
| Lopinavir | ||||||
| On/off | 4/1 | 8/4 | 9/3 | 3/2 | 7/3 | 12[8]/30 |
| ∆G ave | − 23.0 (4.0) | − 29.4 (6.2) | − 28.5 (5.3) | − 20.8 (5.3) | − 25.6 (5.8) | − 34.5 (6.6) |
| ∆G min | − 32.7 | − 39.1 | − 34.6 | − 31.3 | − 30.4 | − 50 |
| Nelfinavir | ||||||
| On/off | 6/1 | 4/1 | 1/1 | 8/1 | 4/1 | 3[9]/21 |
| ∆G ave | − 31.2 (8.9) | − 24.2 (3.6) | – | − 26.6 (5.8) | − 33.3 (3.9) | − 25.6 (4.4) |
| ∆G min | − 51.5 | − 30.3 | – | − 40.6 | − 37.6 | − 36.7 |
| Ritonavir | ||||||
| On/off | 9/3 | 5/0 | 3/2 | 10/4 | 7/5 | 14[5]/34 |
| ∆G ave | − 40.0 (6.4) | − 38.2 (7.9) | − 27.6* (2.9) | − 45.3 (11.0) | – | − 42.1 (4.5) |
| ∆G min | − 51.5 | − 53.6 | − 25.8 | − 63.9 | – | − 50.5 |
| Saquinavir | ||||||
| On/off | 6/2 | 9/3 | 3/3 | 6/0 | 3/1 | 8[8]/26 |
| ∆G ave | − 32.6 (4.8) | − 35.3 (9.8) | − 25.8* (4.3) | − 32.3 (6.8) | – | − 20.8 (3.3) |
| ∆G min | − 39.1 | − 47.8 | − 30.3 | − 44.4 | – | − 29.4 |
| Tipranavir | ||||||
| On/off | 10/3 | 0/0 | 3/2 | 7/3 | 7/3 | 11[8]/27 |
| ∆G ave | − 25.9 (7.6) | – | − 21.4 (3.1) | − 23.8 (6.6) | − 24.0 (7.5) | − 24.4 (5.3) |
| ∆G min | − 42.6 | – | − 34.2 | − 36.9 | − 34.1 | − 36.9 |
The classification was based on the clustering analysis described in Supplementary information C. The events were counted after smoothing by taking majority for 71 data points, sampled every 0.2 ns. The number in square brackets in the others column indicates the number of trajectories that stayed on it during whole simulation period. The sites printed in bold type had the largest fraction at final states (the largest number of “on” events minus “off” events), except for the others category, the sites printed in italic type had the smallest ratio of off/on events, and the sites printed in bold and italic type satisfied both the conditions. The rows “∆G avg” and “∆G min” indicate the average (with the standard deviation in parenthesis) and minimum binding free energy in a unit of kcal/mol, respectively. The energies were omitted when the solvent-accessible surface area (SASA) of each ligand was above 50% of the SASA of the solvated ligand (Supplementary Information E). The lowest energies among sites 1–5 are printed in bold type. The average energies were calculated from the last 100 ns, except for values marked by asterisk, which were taken from the full trajectories. The minimum energies were taken from the averaged energies over 15 continuous points, every 0.2 ns of the whole 200 ns trajectory.