The conformational heterogeneity of the tumor suppressor p53 is tuned by
punctual mutations
Abstract
Conformational heterogeneity of the p53 tumor suppressor, wild-type and
mutated forms, was investigated by computational modelling combined with
all atoms Molecular Dynamics (MD) simulations. Four different punctual
mutations (p53R175H, p53R248Q, p53R273H, p53R282W), which are known to
affect the DNA binding and belong to the most frequent hot-spot
mutations in human cancers, were taken into consideration. The MD
trajectories of the wild-type and mutated p53 forms were analysed by
Essential Dynamics, to extract relevant collective motions. The same
trajectories were also analysed by the frustration method which allows
to evaluate the degeneracy of the energy landscape. We found that
punctual mutations can modulate the collective motions of p53 at
different extent according to the specific mutation. Furthermore,
mutations can affect the frustration level of p53 specially in the
regions involved in the binding to physiological ligands. The regions of
p53 with larger collective motions are also characterized by a high
frustration level. The regions of p53 characterized by a high
frustration level are also largely involved in wide collective motions.
Such a correlation is discussed in connection with the intrinsic
disordered character of p53 and also with its central functional role.