Molecular dynamics of the asymmetric dimers of EGFR: simulations on the active and inactive conformations of the kinase domain.

Abnormal activation of EGFR is associated with human cancer, and thus it is a key target for inhibition in cancer therapy. There is evidence suggesting that the activation mechanism of EGFR is based upon the formation of the asymmetric dimer of the kinase domains. Here, we performed MD simulations on the asymmetric dimer for both active and inactive conformations of EGFR kinase domain to investigate flexibility and intrinsic motions of the proteins. Simulations of the active conformation showed that the formation of the asymmetric dimer changes the dynamics of EGFR kinase domain by suppressing fluctuation of the protein and altering the direction of motion of the protein. In contrast, the asymmetric dimerization of the inactive conformation does not alter the overall fluctuation of the kinase domain and does not initiate destabilizing of the inactive structure. We also investigated the intermolecular interactions in the EGFR asymmetric dimers and found that in the active conformation the interactions are dominated by loop-loop contacts rather than those from the helix-helix interactions. In contrast, helix-helix interaction seemed to be more significant for the inactive kinase structure. This work helps us to better understand the conformational flexibility and dynamics of the EGFR kinase domain, as well as provides information that may be useful to develop newer classes of inhibitors that can block allosteric sites rather than the more traditional catalytic site.