10.1021/acs.jctc.5b01221.s001
Jiyong Park
Jiyong
Park
Joseph
J. McDonald
Joseph
J.
McDonald
Russell C. Petter
Russell C.
Petter
K. N. Houk
K. N.
Houk
Molecular Dynamics Analysis of Binding of Kinase Inhibitors
to WT EGFR and the T790M Mutant
American Chemical Society
2016
ATP binding energy
metadynamics MD simulations
T 790M
T 790M mutation
NAMD
AEE 788
inhibitor binding pocket
Molecular Dynamics Analysis
TI
T 790M Mutant Epidermal growth factor receptor
WT EGFR
T 790M point mutation
2016-03-24 00:00:00
Journal contribution
https://acs.figshare.com/articles/journal_contribution/Molecular_Dynamics_Analysis_of_Binding_of_Kinase_Inhibitors_to_WT_EGFR_and_the_T790M_Mutant/3153490
Epidermal
growth factor receptor (EGFR) inhibitors interrupt EGFR-dependent
cellular signaling pathways that lead to accelerated tumor growth
and proliferation. Mutation of a threonine in the inhibitor binding
pocket, known as the “gatekeeper”, to methionine (T790M)
confers acquired resistance to several EGFR-selective inhibitors.
We studied interactions between EGFR inhibitors and the gatekeeper
residues of the target protein. Thermodynamic integration (TI) with
Amber14 indicates that the binding energies of gefitinib and AEE788
to the active state of the T790M mutant EGFR is 3 kcal/mol higher
than to the wild type (WT), whereas ATP binding energy to the mutant
is similar to the WT. Using metadynamics MD simulations with NAMD
v2.9, the conformational equilibrium between the inactive resting
state and the catalytically competent activate state was determined
for the WT EGFR. When combined with the results obtained by Sutto
and Gervasio, our simulations showed that the T790M point mutation
lowers the free energy of the active state by 5 kcal/mol relative
to the inactive state of the enzyme. Relative to the WT, the T790M
mutant binds gefitinib more strongly. The T790M mutation is nevertheless
resistant due to its increased binding of ATP. By contrast, the binding
of AEE788 to the active state causes a conformational change in the
αC-helix adjacent to the inhibitor binding pocket, that results
in a 2 kcal/mol energy penalty. The energy penalty explains why the
binding of AEE788 to the T790M mutant is unfavorable relative to binding
to WT EGFR. These results establish the role of the gatekeeper mutation
on inhibitor selectivity. Additional molecular dynamics (MD) simulations,
TI, and metadynamics MD simulations reveal the origins of the changes
in binding energy of WT and mutants.