Table 5.

Individual energy terms of MM-PBSA binding free energies of afatinib and gefitinib binding to EGFR and its mutants

AA change	ΔEVDW ± SD	ΔEeel ± SD	± SD	± SD	−TΔS ± SD	ΔGbind ± SD	ΔΔGbind
Afatinib
Wild type	−61.40 ± 0.10	−48.15 ± 0.18	73.63 ± 0.27	−4.98 ± 0.00	−26.44 ± 0.04	−10.82 ± 0.11	0.00
L858R	−57.30 ± 0.07	−39.64 ± 0.11	63.08 ± 0.35	−4.86 ± 0.01	−25.08 ± 0.05	−9.82 ± 0.15	1.00
T790M	−61.81 ± 0.12	−51.89 ± 0.04	75.89 ± 0.24	−4.89 ± 0.00	−26.59 ± 0.04	−12.52 ± 0.04	-1.70
L858R/T790M	−56.20 ± 0.19	−44.91 ± 0.51	67.44 ± 0.63	−4.81 ± 0.01	−25.08 ± 0.01	−9.70 ± 0.09	1.12
G719S	−61.60 ± 0.07	−49.44 ± 0.13	72.29 ± 0.17	−5.08 ± 0.00	−27.02 ± 0.01	−13.41 ± 0.06	-2.53
L858R/G719S	−59.91 ± 0.17	−44.81 ± 0.42	69.70 ± 0.73	−5.03 ± 0.01	−26.18 ± 0.02	−9.95 ± 0.42	0.87
D761Y	−59.70 ± 0.15	−43.60 ± 0.32	68.53 ± 0.33	−5.00 ± 0.01	−25.79 ± 0.07	−10.18 ± 0.16	0.64
L858R/D761Y	−60.82 ± 0.21	−43.61 ± 0.62	68.08 ± 0.41	−4.95 ± 0.01	−26.34 ± 0.05	−11.18 ± 0.29	-0.36
L861Q	−57.05 ± 0.19	−45.41 ± 0.19	68.56 ± 0.21	−4.85 ± 0.01	−25.25 ± 0.05	−9.62 ± 0.02	1.20
L858R/L861Q	−57.84 ± 0.41	−44.37 ± 0.22	69.58 ± 0.27	−4.93 ± 0.00	−25.50 ± 0.00	−7.71 ± 0.31	3.11
Gefitinib
Wild type	−55.40 ± 0.14	−13.78 ± 0.18	40.40 ± 0.43	−4.52 ± 0.01	−24.05 ± 0.02	−9.25 ± 0.36	0.00
L858R	−55.89 ± 0.24	−13.48 ± 0.22	38.70 ± 0.04	−4.62 ± 0.01	−24.38 ± 0.07	−10.92 ± 0.21	-1.67
T790M	−57.62 ± 0.24	−15.56 ± 0.49	41.91 ± 0.35	−4.45 ± 0.01	−24.84 ± 0.07	−10.88 ± 0.05	-1.63
L858R/T790M	−52.81 ± 0.29	−11.59 ± 0.34	36.72 ± 0.28	−4.28 ± 0.01	−23.32 ± 0.03	−8.64 ± 0.20	0.61
G719S	−54.02 ± 0.10	−23.07 ± 0.18	50.34 ± 0.55	−4.33 ± 0.01	−23.75 ± 0.03	−7.33 ± 0.51	1.92
L858R/G719S	−53.62 ± 0.41	−12.49 ± 0.33	39.51 ± 0.18	−4.40 ± 0.01	−23.72 ± 0.08	−7.29 ± 0.26	1.96
D761Y	−54.15 ± 0.13	−15.11 ± 0.25	41.75 ± 0.34	−4.57 ± 0.01	−23.78 ± 0.03	−8.30 ± 0.28	0.95
L858R/D761Y	−54.48 ± 0.31	−17.72 ± 0.15	45.08 ± 0.60	−4.39 ± 0.01	−23.85 ± 0.08	−7.66 ± 0.19	1.59
L861Q	−51.40 ± 0.22	−17.36 ± 0.17	42.07 ± 0.41	−4.31 ± 0.01	−22.94 ± 0.06	−8.06 ± 0.18	1.19
L858R/L861Q	−52.43 ± 0.04	−13.57 ± 0.31	38.82 ± 0.43	−4.23 ± 0.00	−23.24 ± 0.05	−8.18 ± 0.74	1.07

Note: All energy terms are in kcal/mol. The relative binding free energy of a mutant, ΔΔGbind, is calculated by subtracting the MM-PBSA binding free energy of the wild type from that of the mutant. The following is the detailed description of energy terms listed in the table. ΔE_VDW: van der Waals energy. ΔE_eel: electrostatic energy. : the polar part of the solvation free energy. : the nonpolar part of the solvation free energy. −TΔS: the entropic contribution to the binding free energy. ΔG_bind, the binding free energy, which is the sum of the above individual energy terms. ΔΔG_bind is the relative binding free energy compared to the wild type. SD: standard deviation.