jp8b09029_si_001.pdf (20.68 MB)
Computational Studies of Intrinsically Disordered Proteins
journal contribution
posted on 2018-10-29, 00:00 authored by Vy T. Duong, Zihao Chen, Mahendra T. Thapa, Ray LuoFrequently elusive
to experimental characterizations, intrinsically
disordered proteins (IDPs) can be probed using molecular dynamics
to provide detailed insight into their complex structure, dynamics,
and function. However, previous computational studies were often found
to disagree with experiment due to either force field biases or insufficient
sampling. In this study, nine unstructured short peptides and the
HIV-1 Rev protein were simulated and extended to microseconds to assess
these limitations in IDP simulations. In short peptide simulations,
a tested IDP-specific force field ff14IDPSFF outperforms
its generic counterpart ff14SB as agreement of simulated
NMR observables with experiment improves, though its advantages are
not clear-cut in apo Rev simulations. It is worth noting that sampling
is probably still not sufficient in the ff14SB simulations
of apo Rev even if 10 ms have been collected. This indicates that
enhanced sampling techniques would greatly benefit IDP simulations.
Finally, detailed structural analyses of apo Rev conformations demonstrate
different secondary structural preferences between ff14SB (helical) and ff14IDPSFF (random coil). A natural
next step is to ask a more quantitative question: whether ff14SB is too ordered or ff14IDPSFF is
too disordered in simulations of more complex IDPs such as Rev. This
requires further quantitative analyses both experimentally and computationally.