Table 3.
Thermodynamic changes with increased simulation time
| Method | Thermodynamic integration | Hamiltonian replica exchange | |||
|---|---|---|---|---|---|
| Time (ps/LP) | ΔG hysteresis (kJ/mol) | ΔG cycle (kJ/mol) | ΔΔG affinity (kJ/mol) | ΔG cycle (kJ/mol) | ΔΔG affinity (kJ/mol) |
| 200.0 | 68.4 ± 7.5 | 9.7 ± 4.5 | −3.7 ± 4.5 | 0.9 ± 4.6 | −3.4 ± 4.6 |
| 400.0 | 58.5 ± 9.4 | 8.0 ± 7.6 | −6.6 ± 5.4 | 0.1 ± 4.2 | −2.9 ± 4.2 |
| 600.0 | 55.6 ± 8.7 | 7.2 ± 6.9 | −7.6 ± 4.9 | 1.1 ± 4.2 | −4.3 ± 4.2 |
| 800.0 | 53.6 ± 8.3 | 6.8 ± 6.4 | −8.2 ± 4.5 | 0.4 ± 3.8 | −4.8 ± 3.8 |
| 1,000.0 | 51.8 ± 8.1 | 8.0 ± 6.2 | −8.0 ± 4.4 | 2.5 ± 3.6 | −4.4 ± 3.6 |
Summed hysteresis for TI (ΔG hysteresis), averaged main cycle closure (ΔG cycle), and relative affinity difference between wild type and mutant CYP2D6 (ΔΔG affinity), calculated from the ensemble averages after a given simulation time length per λ point (ps/LP)