Predicting the Three-Dimensional Structure of the c-KIT Proto-Oncogene Promoter and the Dynamics of Its Strongly Coupled Guanine Quadruplexes

Guaninequadruplexes (G4s) play essential protective and regulatoryroles within cells, influencing gene expression. In several gene-promoterregions, multiple G4-forming sequences are in close proximity andmay form three-dimensional arrangements. We analyze the interplayamong the three neighboring G4s in the c-KIT proto-oncogenepromoter (WK1, WSP, and WK2). We highlight that the three G4s arestructurally linked and their cross-talk favors the formation of aparallel structure for WSP. Relying on all-atom molecular dynamicsimulations exceeding the mu s time scale and using enhanced samplingmethods, we provide the first computationally resolved structure ofa well-organized G4 cluster in the promoter of a crucial gene involvedin cancer development. Our results indicate that neighboring G4s influencetheir mutual three-dimensional arrangement and provide a powerfultool to predict and interpret complex DNA structures that can ultimatelybe used as a starting point for drug discovery.