The αC-helix is depicted in cyan, while the A-loop in orange. The point of deleted residues in the ΔELREA mutant is indicated with a red dot. In the case of the point mutation L858R, and the two …
(A) active conformation in which the A-loop assumes an extended conformation, forming usually a β-strand (β9) with residues of the C-lobe, the αC-helix is found in the αC-in conformation, and the …
Simple moving averaged time series of the distance between two salt-bridge-forming residue pairs K745-E762 and D855-E762 over the course of the unbiased simulations starting from the monomeric …
Cluster of hydrophobic residues (blue spheres) whose side chains pack together to stabilize the two-turn helix (yellow) of the A-loop and the Src-like inactive conformation (PDB ID: 2GS7) overall.
Position of the αC-helix in each monomer of the simulated dimers. The distances over the course of the dimeric simulations between K745, E762, and D855, which together probe the position of the …
Representative structures for free energy minima are depicted in cartoon representation. A yellow cross indicates the position of the active conformation (PDB ID: 2GS2) in the explored CV space, …
Representative structures for two main conformations found in the deepest minimum are depicted in cartoon representation. The interaction of R858 with E758 and E762 is responsible for the secondary …
(A) Important interactions of L858R with neighboring residues that are maintained over the course of the unbiased simulations of the monomeric L858R EGFR. The estimation of the time fraction that …
Representative structures of the two main conformations found in the deepest minima are depicted in cartoon representation. A yellow cross indicates the position of the active conformation (PDB ID: …
Key interactions around the inserted residues in the D770-N771insNPG mutant as seen in (A) the ligand-bound active conformation of the mutant (PDB ID: 4LRM), and in (B) the homology model of the …
Simple moving averaged time series of the interactions of R776/9 with D770 (A) and A767 (B) over the course of the unbiased simulations starting from the monomeric active (top row) and Src-like …
Distribution of the radius of gyration (Rg) of the receiver and the activator kinases over the course of the unbiased simulations of the asymmetric dimer of D770-N771insNPG EGFR. The increased Rg of …
Representative structures of the main conformations found in the free energy minima are depicted in cartoon representation. A yellow cross indicates the position of the active conformation (homology …
(A) Side and top view of the WT and A763-Y764insFQEA asymmetric dimer interface around the αC-helix (receiver monomer) and H-helix (activator monomer). F760 of A763-Y764insFQEA is accommodated in …
Representative structures of the main conformations found in the free energy minima are depicted in cartoon representation. A yellow cross indicates the position of the active conformation (homology …
The activation loop of each structure has been highlighted to show the similarity in the adopted conformation.
Distribution of the distance between residues of the αC-helix of the receiver kinase and I-helix of the activator kinase over the course of the unbiased simulations of the ΔELREA asymmetric dimer. …
(A) RMSD change with respect to the active and Src-like inactive conformation during the SMD simulation of the A763-Y764insFQEA EGFR. The SMD simulation was initiated from the active conformation …
PTmetaD simulations convergence check for the ΔELREA-EGFR. (A) Time series per replica of the three CVs that were biased during the PTmetaD simulation. Following the progression of the predefined …
Mapping of the conformational space sampled during the unbiased simulations of the monomeric EGFR to the space sampled during the PTmetaD simulations as projected to two out of the three CVs that …
Minimum energy path connecting the active to Src-like inactive conformation.
N/C-lobe separation (A) during the unbiased simulations of the monomeric form starting from the active conformation, (B) the receiver monomer during the unbiased simulations of the homodimeric form, …
Ensemble of conformations from the PTmetaD simulations of the activating mutant (A) L858R and (B) A763-Y764insFQEA in the αC-in and αC-out conformations depicted in gray tubes and superimposed with …
The reported times correspond to the simulation time of each independent unbiased simulation.
System | Starting conformation | Total simulation time (ns) |
---|---|---|
WT | active | 1000 |
active | 1000 | |
Src-like inactive | 1000 | |
Src-like inactive | 1000 | |
L858R | active | 1000 |
Src-like inactive | 1000 | |
A763-Y764insFQEA | active | 1000 |
Src-like inactive | 1000 | |
D770-N771insNPG | active | 1000 |
Src-like inactive | 1000 | |
ΔELREA | active | 1000 |
Src-like inactive | 1000 | |
[1ex] |
The reported times correspond to the simulation time of each independent unbiased simulation.
System | Starting conformation | Total simulation time (ns) |
---|---|---|
WT | asymmetric dimer | 4000 |
symmetric dimer | 4000 | |
L858R | asymmetric dimer | 4000 |
A763-Y764insFQEA | asymmetric dimer | 4000 |
D770-N771insNPG | asymmetric dimer | 4000 |
ΔELREA | asymmetric dimer | 4000 |