Molecular docking and molecular dynamics simulations reveal the clinical resistance of the gatekeeper mutation V564F of FGFR2 against Infigratinib

Figures & data

Figure 1. The two-dimensional Chemical structure of Infigratinib.

Figure 2. Overview of the crystal structure of FGFR2 kinase domain (PDB ID: 3RI1).

The α-helices, β-strands, and loops are colored red, yellow, and gray, respectively. The hinge domain is colored green spheres. The P-loop, helix αC, and A-loop are colored blue, purple, and orange, respectively.

Figure 3. The docked conformation of the FGFR2 kinase domain with Infigratinib. The hinge residues Glu565 and Ala567 are Depicted by sticks. Hydrogen bonds are shown by yellow dotted lines.

Figure 4. RMSD values of the Cα atoms of the FGFR2 kinase domain (a) and the heavy atoms of Infigratinib (b) for the FGFR2-WT (a) and FGFR2-V564F (b) in the process of MD simulations.

Figure 5. The Cα RMSF of the FGFR2-WT and FGFR2-V564F mutant.

Figure 6. Correlations between the Cα atoms of the FGFR2-WT (a) and the FGFR2-V564F (b) mutant. Correlation values are represented by a color gradient of blue to red.

Table 1. Binding free energies of Infigratinib in FGFR2-WT and FGFR2-V564F (kcal/mol).

	WT/ Infigratinib	V564F/Infigratinib
ΔEvdW	−59.45 ± 4.27	−55.86 ± 3.50
ΔEelec	−20.80 ± 5.14	−12.56 ± 4.34
ΔGSA	−7.18 ± 0.39	−6.66 ± 0.36
ΔGGB	29.59 ± 4.86	25.50 ± 4.02
ΔGbinding	−57.84 ± 6.08	−49.57 ± 4.73

ΔE_vdW: Van der Waals energy; ΔE_elec: electrostatic energy; ΔG_GB: electrostatic contribution to solvation; ΔG_SA: non-polar contribution to solvation; ΔG_binding: binding free energy.

Figure 7. The energetic differences of the residue contributions to the binding free energies between the FGFR2-WT and FGFR2-V564F mutant systems (ΔΔG=ΔG_WT − ΔG_V564F).

Table 2. Percent of occurrence data (%) for hydrogen bonds between Ala567 and Infigratinib.

Hydrogen bonds	WT	V564F
Ala567-CO – Phenylamine NH of Infigratinib	93.2	54.2
Ala567-NH – Pyrimidine nitrogen of Infigratinib	94.2	78.2

Figure 8. The distance (Å) between the pyrimidine C(2)-H of Infigratinib and the backbone carbonyl oxygen of Glu565 for the FGFR2-WT (a) and FGFR2-V564F (b) in the process of MD simulations.

Figure 9. Free energy landscape for the FGFR2-WT (a) and FGFR2-V564F (b). the unit of the free energy landscape is kcal/mol.

Figure 10. The Representative structures of FGFR2-WT (a) and FGFR2-V564F (b). hydrogen bonds are colored by yellow dotted lines and the key residues are shown by sticks.