Molecular dynamics simulations of intrinsically disordered proteins p53TAD and Pup

Intrinsically disordered proteins (IDPs) are highly dynamic systems that
play an important role in cell signaling processes and their misfunction
often causes human disease. Proper understanding of IDP function not only
requires the realistic characterization of their three-dimensional
conformational ensembles at atomic-level resolution but also of the time
scales of interconversion between their conformational substates. Large
sets of experimental data are often used in combination with molecular
modeling to restrain or bias models to improve agreement with experiment.
It is shown here for the N-terminal transactivation domain of p53 (p53TAD)
and Pup how the latest advancements in molecular dynamics (MD) simulations
methodology produces native conformational ensembles by combining replica
exchange with series of microsecond MD simulations. They closely reproduce
experimental data at the global conformational ensemble level, in terms of
the distribution properties of the radius of gyration tensor, and at the
local level, in terms of NMR properties including 15N spin relaxation,
without the need for reweighting. The IDP ensembles were analyzed by graph
theory to identify dominant inter-residue contact clusters and
characteristic amino-acid contact propensities. These findings indicate
that modern MD force fields with residue-specific backbone potentials can
produce highly realistic IDP ensembles sampling a hierarchy of nano- and
picosecond time scales providing new insights into their biological
function.