Molecular
simulations of intrinsically disordered proteins (IDPs)
are challenging because they require sampling a very large number
of relevant conformations, corresponding to a multitude of shallow
minima in a flat free energy landscape. However, in the presence of
a binding partner, the free energy landscape of an IDP can be dominated
by few deep minima. This characteristic imposes high demands on the
accuracy of the force field used to describe the molecular interactions.
Here, as a model system for an IDP that is unstructured in solution
but folds upon binding to a structured interaction partner, the transactivation
domain of c-Myb was studied both in the unbound (free) form and when
bound to the KIX domain. Six modern biomolecular force fields were
systematically tested and compared in terms of their ability to describe
the structural ensemble of the IDP. The protein force field/water
model combinations included in this study are AMBER ff99SB-disp with
its corresponding water model that was derived from TIP4P-D, CHARMM36m
with TIP3P, ff15ipq with SPC/Eb, ff99SB*-ILDNP with TIP3P
and TIP4P-D, and FB15 with TIP3P-FB water. Comparing the results from
REST2-enhanced sampling simulations with experimental CD spectra and
secondary chemical shifts reveals that the ff99SB-disp force field
can realistically capture the broad and mildly helical structural
ensemble of free c-Myb. The structural ensembles yielded by CHARMM36m,
ff99SB*-ILDNP together with TIP4P-D water, and FB15 are also mildly
helical; however, each of these force fields can be assigned a specific
subset of c-Myb residues for which the simulations could not reproduce
the experimental secondary chemical shifts. In addition, microsecond-timescale
MD simulations of the KIX/c-Myb complex show that most force fields
used preserve a stable helix fold of c-Myb in the complex. Still,
all force fields predict a KIX/c-Myb complex interface that differs
slightly from the structures provided by NMR because several NOE-derived
distances between KIX and c-Myb were exceeded in the simulations.
Taken together, the ff99SB-disp force field in the first place but
also CHARMM36m, ff99SB*-ILDNP together with TIP4P-D water, and FB15
can be suitable choices for future simulation studies of the coupled
folding and binding mechanism of the KIX/c-Myb complex and potentially
also other IDPs.
A common feature of intrinsically disordered proteins (IDPs) is a disorder-to-order transition upon binding to other proteins, which has been tied to multiple benefits, including accelerated association rates or binding...
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