c-MYC, part of the MYC family of transcription factors, is often deregulated in cancer, and since the early 1980’s has been identified as a prime oncogenic factor. Despite much research interest, c-MYC’s structural dynamics remain largely uncharted due to its intrinsic structural disorder. Disordered proteins are challenging to study using solely structural experimental methods, thus lately attention has turned towards the development of reliable in-silico methods to get an accurate molecular description. Molecular Dynamics simulations, commonly and successfully used to study globular proteins, can also be optimised to correctly reproduce natural protein disorder. The simulation results were assessed for convergence and conformational equilibrium, achieved by comparing the c-MYC’s Molecular Dynamics conformational landscape to similar data derived from an abundantly sampled probabilistic distribution. After the preparatory and validation work, the efforts turned to the appraisal of c-MYC’s first 88 amino acids. The revelation of its conformational states and structural dynamics opened the door for drug discovery and proof-of-concept that c-MYC should not be considered ‘undruggable’. Further exploration into the protein first 150 residues, corresponding to its transactivation domain, uncovered important structural dynamics controlled by key phosphodegron residues. Phosphorylation and mutagenesis studies demonstrated how these control mechanisms, which serve to modulate accessibility to crucial regions, are facilitated by isomerisation events within the phosphodegron. Overarchingly, this study substantiates the robustness of well-parameterised computational simulations, and machine learning methods, in uncovering the workings of otherwise difficult to study disordered proteins.Open Acces
