Table 1.
Comparison of experimental IC50 changes and predicted mutational energies (ΔΔG).
| Substitution | α4β2 nAChR | α3β2 nAChR | α7 nAChR | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| IC50 Ratio a | ΔΔG at the α4(+)β2(−) | ΔΔG at the α4(+)α4(−) | IC50 Ratio a | ΔΔG at the α3(+)β2(−) | ΔΔG at the α3(+)α3(−) | IC50 Ratio a | ΔΔG at the α7(+)α7(−) | ||||||
| S7A | 7.6 | −0.2 b | TP c | 0.0 | TP | 0.9 | 0.0 | TP | 0.2 | TP | 2.2 | 0.2 | TP |
| N8A | >17 | 2.3 | TN | 1.8 | FP | 1.4 | 2.2 | TP | 1.8 | TP | > 10 | 1.8 | FP |
| P9A | >17 | 2.7 | TN | 2.9 | TN | 59 | 2.6 | TN | 2.8 | TN | 15 | 2.6 | TN |
| A10S | 0.8 | 0.7 | TP | 0.9 | TP | 6.4 | 1.0 | TP | 1.9 | TP | - | - | - |
| A10T | >20 | 0.8 | FP | 2.5 | TN | >2700 | 2.1 | FP | 3.2 | TN | - | - | - |
| R12A | >17 | 1.8 | FP | 2.5 | TN | 3.6 | 2.2 | TP | 1.2 | TP | 8.3 | 1.5 | TP |
| V13A | 2.0 | 1.3 | TP | 1.5 | TP | 0.2 | 1.1 | TP | 2.3 | TP | 1.9 | 1.6 | TP |
| V13F | >20 | 2.4 | TN | 8.3 | TN | 111 | 2.7 | TN | 10.5 | TN | - | - | - |
| V13W | >20 | 6.7 | TN | 16.2 | TN | >2700 | 8.2 | TN | 16.9 | TN | - | - | - |
| V13L | >20 | −0.5 | FP | −0.7 | FP | >2700 | −0.7 | FP | −0.2 | FP | - | - | - |
| V13I | 1.3 | −0.3 | TP | −0.3 | TP | 3.6 | −0.5 | TP | −0.3 | TP | - | - | - |
| V13S | 1.0 | 2.1 | TP | 1.9 | TP | 0.4 | 1.8 | TP | 2.3 | FN | - | - | - |
| V13T | 1.2 | 1.5 | TP | 1.1 | TP | 1.3 | 1.3 | TP | 1.4 | TP | - | - | - |
| N14A | >17 | 1.5 | FP | −0.2 | FP | 0.4 | 1.7 | TP | 1.9 | TP | 8.7 | 1.2 | TP |
| N15A | >17 | 1.2 | FP | 1.1 | FP | 1.1 | 1.3 | TP | 0.8 | TP | 1.0 | 1.0 | TP |
| N15K | >20 | 0.0 | FP | −0.1 | FP | >2700 | 0.2 | FP | 0.0 | FP | - | - | - |
| N15H | >20 | 1.2 | FP | 2.0 | FP | 44 | 0.9 | FP | 3.4 | TN | - | - | - |
| O16A | 11 | 1.5 | TP | 2.4 | FN | 4.7 | 1.6 | TP | 1.2 | TP | 2.2 | 2.2 | TP |
| H17A | 11 | 0.4 | TP | 0.3 | TP | 0.9 | 0.2 | TP | 0.3 | TP | 0.8 | 0.1 | TP |
| V18A | >17 | 1.4 | FP | 1.2 | FP | 14 | 1.0 | TP | 1.2 | TP | 1.3 | 1.2 | TP |
| V18Y | >20 | 4.2 | TN | 1.8 | FP | >2700 | 3.4 | TN | 1.0 | FP | - | - | - |
| V18Q | >20 | 1.6 | FP | 0.7 | FP | >2700 | 0.6 | FP | 0.7 | FP | - | - | - |
| V18N | 0.4 | 2.0 | TP | 1.1 | TP | >2700 | 1.3 | FP | 1.0 | FP | - | - | - |
| Accuracy | 61% | 57% | 74% | 74% | 90% | ||||||||
| MCC d | 0.42 | 0.27 | 0.52 | 0.48 | 0.67 | ||||||||
a IC50 values are from Millard et al. [20] and Banerjee et al. [21]. b Average ΔΔGs computed with FoldX over three replicate molecular dynamics simulations and 100 frames extracted from each simulation. The standard deviations of the mutational energies predicted over the three simulations are in Supplementary Material Tables S1–S8. c Classification of predictions as TP (True positive), TN (True negative), FP (False positive) and FN (False negative) by considering that IC50 ratios < 15 and predicted energies < 2.3 kcal/mol are labeled “positive” and otherwise labeled “negative”. d Matthews’ correlation coefficient (1.00 is perfect prediction, 0.00 is random prediction).