Kiel, ChristinaBenisty, Hannah, 1986-Lloréns Rico, Verónica, 1989-Serrano Pubull, Luis, 1982-2016-06-032016-06-032016Kiel C, Benisty H, Lloréns-Rico V, Serrano L. The yin-yang of kinase activation and unfolding explains the peculiarity of Val600 in the activation segment of BRAF. Elife. 2016; 5: e12814. DOI 10.7554/eLife.128142050-084Xhttp://hdl.handle.net/10230/26822Many driver mutations in cancer are specific in that they occur at significantly higher rates than - presumably - functionally alternative mutations. For example, V600E in the BRAF hydrophobic activation segment (AS) pocket accounts for >95% of all kinase mutations. While many hypotheses tried to explain such significant mutation patterns, conclusive explanations are lacking. Here, we use experimental and in silico structure-energy statistical analyses, to elucidate why the V600E mutation, but no other mutation at this, or any other positions in BRAF's hydrophobic pocket, is predominant. We find that BRAF mutation frequencies depend on the equilibrium between the destabilization of the hydrophobic pocket, the overall folding energy, the activation of the kinase and the number of bases required to change the corresponding amino acid. Using a random forest classifier, we quantitatively dissected the parameters contributing to BRAF AS cancer frequencies. These findings can be applied to genome-wide association studies and prediction models.application/pdfeng© Kiel et al. This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.Biologia computacionalinfo:eu-repo/semantics/articlehttp://dx.doi.org/10.7554/eLife.12814BiophysicsComputational biologyGenotype-phenotype associationHumanPassenger and driver mutationsStructural biologyStructure-energy calculationsSystems biologyinfo:eu-repo/semantics/openAccess