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. 2020 Mar 21;21(6):2167.
doi: 10.3390/ijms21062167.

Computational Study on the Effect of Inactivating/Activating Mutations on the Inhibition of MEK1 by Trametinib

Jingxuan Zhu  1 , Congcong Li  1 , Hengzheng Yang  1 , Xiaoqing Guo  1 , Tianci Huang  1 , Weiwei Han  1
Affiliations

Computational Study on the Effect of Inactivating/Activating Mutations on the Inhibition of MEK1 by Trametinib

Jingxuan Zhu et al. Int J Mol Sci. .

Abstract

Activation of the mitogen-activated protein kinase (MAPK) signaling pathway regulated by human MAP kinase 1 (MEK1) is associated with the carcinogenesis and progression of numerous cancers. In addition, two active mutations (P124S and E203K) have been reported to enhance the activity of MEK1, thereby eventually leading to the tumorigenesis of cancer. Trametinib is an MEK1 inhibitor for treating EML4-ALK-positive, EGFR-activated, and KRAS-mutant lung cancers. Therefore, in this study, molecular docking and molecular dynamic (MD) simulations were performed to explore the effects of inactive/active mutations (A52V/P124S and E203K) on the conformational changes of MEK1 and the changes in the interaction of MEK1 with trametinib. Moreover, steered molecular dynamic (SMD) simulations were further utilized to compare the dissociation processes of trametinib from the wild-type (WT) MEK1 and two active mutants (P124S and E203K). As a result, trametinib had stronger interactions with the non-active MEK1 (WT and A52V mutant) than the two active mutants (P124S and E203K). Moreover, two active mutants may make the allosteric channel of MEK1 wider and shorter than that of the non-active types (WT and A52V mutant). Hence, trametinib could dissociate from the active mutants (P124S and E203K) more easily compared with the WT MEK1. In summary, our theoretical results demonstrated that the active mutations may attenuate the inhibitory effects of MEK inhibitor (trametinib) on MEK1, which could be crucial clues for future anti-cancer treatment.

Keywords: MEK1; allosteric channel; docking; molecular dynamic simulations; steered molecular dynamic simulations; trametinib.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
The interactions between protein and ligand in allosteric and ATP binding pockets respectively. (A) The allostric binding site and ATP binding site in MAP kinase 1 (MEK1) (PDB Id 3SLS). (B) The 2D structure of tramctinib. (C) Tramctinib docked to the allosteric site. (D) Tramctinib docked to the ATP site. (E) The active residues around tramctinib binding to the allosteric site. (F) The active residues around tramctinib binding to the ATP site.
Figure 2
Figure 2
Stability analysis for WT MEK1 and three mutants. (A) The root-mean-square deviation (RMSD) plot during 500 ns MD simulations, (B) the relative frequency of RMSD plot, (C) the average RMSD value.
Figure 3
Figure 3
Dynamic changes of the secondary structure profile for (A) Activation segment and catalytic loop of WT and mutant MEK1 throughout the simulation. The color bar represented different secondary structures as follow: coil [C], π_helix [I], 310_helix [G], α_helix [H], β_Bridge [B], β_bugle [E], turn [T]. (B) Functional classification of MEK1 sequence. (C) The 3D structure of MEK1(PDB code 3SLS) with highlighted activation segment and catalytic loop.
Figure 4
Figure 4
The subnetwork analysis of protein-ligand interaction. The subnetwork between protein and trametinib in (A) WT, (B) A52V mutant, (C) E203K mutant and (D) P124S mutant MEK1.
Figure 5
Figure 5
Dynamical cross-correlation map (DCCM) for the 500 ns molecular dynamic (MD) trajectories of (A) WT, (B) A52V mutant, (C) E203K mutant and (D) P124S mutant MEK1. Positive regions (colored in red) indicated strongly correlated residue motions, whereas negative regions (colored in blue) indicated anti-correlated movements.
Figure 6
Figure 6
Motions of WT and mutant MEK1 based on the first PC for (A) WT, (B) A52V mutant, (C) E203K mutant and (D) P124S mutant MEK1. The arrows represent the directions and amplitudes of the movements.
Figure 7
Figure 7
The surrounding residues for (A) ATP and (B) allosteric channels.
Figure 8
Figure 8
Comparison of the channels about WT, A52V, P124S and E203K complexes. (A–D) The top ranked collective allosteric channels identified by CAVER 3.0 according to the 500 ns MD simulations trajectories. (E) The bottleneck of allosteric channel. (F) The length of allosteric channel. (G) The curvature of allosteric channel.
Figure 9
Figure 9
The changes of the active mutations’ mode. (A) The directions of allosteric channel and ATP channel. (B,C) The four residues located at the allosteric channel and faced toward each other. (D) The distance between the center of mass of His100 and Val224. (E) The distance between the center of mass of Ser194 and Ile216.
Figure 10
Figure 10
The dissociation process of trametinib from (A) WT, (B) A52V, (C) E203K and (D) P124S MEK1.
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