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. 2013;8(2):e55793.
doi: 10.1371/journal.pone.0055793. Epub 2013 Feb 20.

Computational analysis of KRAS mutations: implications for different effects on the KRAS p.G12D and p.G13D mutations

Chih-Chieh Chen  1 , Tze-Kiong Er, Yen-Yi Liu, Jenn-Kang Hwang, Maria Jesus Barrio, Maximiliano Rodrigo, Enrique Garcia-Toro, Marta Herreros-Villanueva
Affiliations

Computational analysis of KRAS mutations: implications for different effects on the KRAS p.G12D and p.G13D mutations

Chih-Chieh Chen et al. PLoS One. 2013.

Abstract

Background: The issue of whether patients diagnosed with metastatic colorectal cancer who harbor KRAS codon 13 mutations could benefit from the addition of anti-epidermal growth factor receptor therapy remains under debate. The aim of the current study was to perform computational analysis to investigate the structural implications of the underlying mutations caused by c.38G>A (p.G13D) on protein conformation.

Methods: Molecular dynamics (MD) simulations were performed to understand the plausible structural and dynamical implications caused by c.35G>A (p.G12D) and c.38G>A (p.G13D). The potential of mean force (PMF) simulations were carried out to determine the free energy profiles of the binding processes of GTP interacting with wild-type (WT) KRAS and its mutants (MT).

Results: Using MD simulations, we observed that the root mean square deviation (RMSD) increased as a function of time for the MT c.35G>A (p.G12D) and MT c.38G>A (p.G13D) when compared with the WT. We also observed that the GTP-binding pocket in the c.35G>A (p.G12D) mutant is more open than that of the WT and the c.38G>A (p.G13D) proteins. Intriguingly, the analysis of atomic fluctuations and free energy profiles revealed that the mutation of c.35G>A (p.G12D) may induce additional fluctuations in the sensitive sites (P-loop, switch I and II regions). Such fluctuations may promote instability in these protein regions and hamper GTP binding.

Conclusions: Taken together with the results obtained from MD and PMF simulations, the present findings implicate fluctuations at the sensitive sites (P-loop, switch I and II regions). Our findings revealed that KRAS mutations in codon 13 have similar behavior as KRAS WT. To gain a better insight into why patients with metastatic colorectal cancer (mCRC) and the KRAS c.38G>A (p.G13D) mutation appear to benefit from anti-EGFR therapy, the role of the KRAS c.38G>A (p.G13D) mutation in mCRC needs to be further investigated.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. Molecular modeling of Human KRAS.
The structure contains three sensitive sites: the P-loop (green), the switch I region (blue) and the switch II (red). The GTP and the Mg2+ ion are shown by ball-and-stick representations.
Figure 2
Figure 2
The molecular dynamics trajectories for: (A) Comparison of the RMSD plots of the sensitive sites (P-loop, switch I and II regions) of WT, G12D and G13D structures with respect to the initial conformation during the course of the simulation; (B) the pocket distances between the mass center of residues 12–13 and the mass center of residues 32–34 for WT, G12D, and G13D, respectively.
Figure 3
Figure 3. Analysis of atomic fluctuations.
The structures of (A) WT, (B) G12D and, (C) G13D KRAS proteins are drawn in cartoon putty representations at the P-loop, switch I and II regions; blue represents the lowest and red the highest B-factor value. In addition, the size of the tube reflects the value of the B-factor, in that the larger the B-factor, the thicker the tube. The structures in the other regions are colored in white and displayed in cartoon tube representation, where the size of the tube is independent of the B-factors.
Figure 4
Figure 4. Distributions of docking scores.
The docking scores for WT (blue), G12D (red) and G13D (green) KRAS proteins docked with GTP are shown in different colors.
Figure 5
Figure 5. Free energy profiles determined for the binding of GTP with WT (blue), G12D (red) and G13D (green).
The reaction coordinate is defined as the distance between the mass center of the GTP and the mass center of the WT, G12D, and G13D KRAS proteins, respectively.
See this image and copyright information in PMC

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Grants and funding

This study was supported by a grant from the Kaohsiung Medical University Research Foundation (KMUH101-1M68). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.