Impact of Arg175His mutation on the dynamical patterns of full-length
human p53 protein
Abstract
p53, a tumor suppressor protein, is essential for preventing cancer
development. Although individual domains of the human p53 have been well
analyzed, no study has experimentally revealed a full-length structure
of human wild-type p53 protein at atomistic level. The presence of all
human p53 domains in one structure will help in showing the correlated
interactions among these domains, thus, leading to enhance our
understanding about the dynamics of this protein and its mutant forms.
In this study we have modeled five human p53 forms, namely, inactive,
distal-active, proximal-active, distal-mutant, and proximal-mutant
forms. These forms have been investigated in this study by gaussian
accelerated molecular dynamics simulations in OPC water model at
physiological temperature and pH. On the basis of the observed dynamical
patterns, all wild-type forms can achieve better conformational
stability through dimerization or tetramerization process. The dynamical
patterns and free-energy profiles of the wild-type forms highlight the
most vulnerable sites to mutations; that is, p53–DNA and p53–p53
interfaces. On the other hand, principal component and clustering
analysis methods on Arg175His mutant forms reveal two distinct
conformational states (clusters); extended and compact clusters. The two
clusters of each mutant form reveal negative cavities near the mutation
site, which can be used for drug screening studies. The observed compact
structures in the conformations of Arg175His mutant forms may indicate
formation of aggregation.