Resistance mechanism of the oncogenic β3-αC deletion mutation in BRAF kinase to dabrafenib and vemurafenib revealed by molecular dynamics simulations and binding free energy calculations.

BRAF kinase is an essential target for anti-cancer drug development. Emergence of the β3-αC loop deletion mutation (ΔNVTAP) in BRAF kinase frequently occurred in human cancers seriously compromises the therapeutic efficacy of some BRAF kinase inhibitors, such as dabrafenib and vemurafenib. However, the mechanism of this resistance is still not well understood. In this study, the influence of the β3-αC deletion mutation on the binding profiles of three BRAF kinase inhibitors (AZ628, dabrafenib, and vemurafenib) with BRAF or BRAF was explored by conventional molecular dynamics (MD) simulations and binding free energy calculations. The simulation results indicated that the β3-αC deletion mutation enhances the flexibility of the αC helix and alters their conformations, which amplify the conformational entropy change (-TΔS) and weaken the interactions between the inhibitors and BRAF. The further per-residue binding free energy decomposition analysis revealed that the ΔNVTAP mutation changed the contributions of a few key residues to the bindings of dabrafenib or vemurafenib, such as L57, L66, W83, C84, F135, G145, and F147, but did not have obvious impact on the contributions of these residues to AZ628. Our results provide valuable clues to understand the mechanisms of drug resistance conferred by the β3-αC deletion mutation.