Table 2. Relative Binding Free Energies Calculated Using Schemes λR2 and λR2-M with Different Highest Effective Temperature (Teff) Compared with Corresponding Experimental Values for All the Inhibitor-Mutant Complexes Studieda.
| ΔΔGcalc |
||||||
|---|---|---|---|---|---|---|
| mutant | drug | λR2b | λR2-Mb | λR2c | λR2-Mc | ΔΔGexp |
| V555M | AZD4547-linear | –2.76(0.12) | –2.70(0.12) | –1.85(0.07) | –1.82(0.06) | –1.75(0.33) |
| AZD4547-bent | –2.07(0.11) | –1.98(0.12) | –1.07(0.07) | –1.11(0.06) | ||
| BGJ-398 | –3.66(0.12) | –3.60(0.12) | –1.92(0.08) | –1.96(0.06) | –1.19(0.08) | |
| TKI258 | –1.17(0.13) | –1.11(0.13) | –1.41(0.08) | –1.42(0.06) | 0.97(0.22) | |
| JNJ42756493 | –3.99(0.16) | –3.92(0.15) | –2.88(0.12) | –2.87(0.11) | –3.08(0.17) | |
| MAE | 1.37 | 1.30 | 0.82 | 0.82 | ||
| RMSE | 1.59 | 1.54 | 1.16 | 1.16 | ||
| I538V | AZD4547-linear | 0.09(0.11) | 0.05(0.11) | –0.12(0.08) | –0.04(0.07) | –2.11(0.32) |
| BGJ-398 | 0.46(0.11) | 0.45(0.11) | 0.01(0.08) | 0.09(0.07) | –0.74(0.21) | |
| TKI258 | 0.47(0.13) | 0.38(0.12) | 0.01(0.08) | 0.12(0.08) | –1.91(0.13) | |
| JNJ42756493 | 0.30(0.12) | 0.28(0.12) | –0.01(0.07) | 0.11(0.07) | –2.18(0.10) | |
| MAE | 2.06 | 2.02 | 1.71 | 1.80 | ||
| RMSE | 2.13 | 2.08 | 1.80 | 1.89 | ||
| N540S | AZD4547-linear | 0.91(0.14) | 0.95(0.14) | 0.72(0.11) | 0.74(0.11) | –0.76(0.33) |
| BGJ-398 | 1.13(0.14) | 1.16(0.13) | 0.67(0.11) | 0.67(0.11) | 0.25(0.19) | |
| TKI258 | 1.02(0.14) | 1.11(0.14) | 0.71(0.12) | 0.72(0.12) | –0.9(0.15) | |
| JNJ42756493 | 1.06(0.14) | 1.11(0.14) | 0.72(0.12) | 0.72(0.12) | –1.75(0.21) | |
| MAE | 1.82 | 1.87 | 1.50 | 1.50 | ||
| RMSE | 1.94 | 2.00 | 1.66 | 1.67 | ||
a
The mean absolute error (MAE) and root mean square error (RMSE) for all complexes of each mutant using each free energy scheme are also shown. Production runs are 4 ns in all cases. All values are in kcal/mol. Statistical uncertainties associated with each value are shown in the brackets.
b
Highest Teff for λ-REST2 simulations is 800 K for receptor and 1500 K for complexes in case of mutants I538V and N540S. In the case of mutant V555M, it is 1500 K for the AZD4547 complexes and 600 K for all other complexes; 600 K is used for the receptor.
c
Highest Teff for λ-REST2 simulations is 1500 K for receptor and 3000 K for complexes.