Molecular dynamics simulations of single amino-acid substitution in BRAF:MEK1 complex
M. Suchý1, P. Havlíčková2, Z. Futera3, M. Fencková1
1Department of Molecular Biology and Genetics, Faculty of Science, University of South Bohemia, České Budějovice
2Department of Chemistry, Faculty of Science, University of South Bohemia, České Budějovice
3Department of Physics, Faculty of Science, University of South Bohemia, České Budějovice
RAS-MAPK pathway is an important signaling pathway, that regulates mitosis, metabolism, motility, survival, apoptosis, and differentiation. Defects in RAS-MAPK signaling can lead to cancer or severe neurodevelopmental disorders. We are focusing on two proteins in this pathway, BRAF and MEK1. Both of them are kinases and MEK1 is a direct substrate of BRAF[1]
We perform molecular dynamics (MD) simulations of eight single amino-acid substitutions in BRAF. They are caused by genetic missense variants that were found in individuals with neurodevelopmental disorders and their pathogenicity and effect on BRAF function is not known. We are simulating the effect of each substitution on ATP binding and BRAF kinase activity in the complex of BRAF:MEK1 (PDB id: 4MNE) with ATP [Figure 1.]. As a reference, we use a well-characterized V600E substitution that increases BRAF activity.[2] We expect to see differences in ATP processing and phosphorylation speed.
Our study may decipher how these mutations
affect BRAF function. The gained knowledge can be used in the development of
BRAF inhibitors, which can block BRAF kinase activity and suppress signaling in
the RAS-MAPK pathway. The knowledge can also be implemented in diagnostics, and
in choosing the right treatment approach and predicting treatment
effectiveness.[3]
Figure 1. Complex BRAF:MEK1 with ATP
1. D. K. Morrison, 2012. MAP Kinase Pathways. Cold Spring Harb Perspect Biol. 4(11)
2. P. Wan, M. Garnett, S. Mark Roe, 2004. Mechanism of Activation of the RAF-ERK Signaling Pathway by Oncogenic Mutations of B-RAF. Cell. 855-867
3. L. Krab, S. Goorden, Y. Elgersma, 2008. Oncogenes on my mind: ERK and MTOR signaling in cognitive diseases. Trends Genet. 498-510