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@ARTICLE{FenollarFerrer:201298,
author = {Fenollar-Ferrer, Cristina and Anselmi, Claudio and
Carnevale, Vincenzo and Raugei, Simone and Carloni, Paolo},
title = {{I}nsights on the acetylated {NF}-κ{B} transcription
factor complex with {DNA} from molecular dynamics
simulations},
journal = {Proteins},
volume = {80},
number = {6},
issn = {0887-3585},
address = {New York, NY},
publisher = {Wiley-Liss},
reportid = {FZJ-2015-03603},
pages = {1560 - 1568},
year = {2012},
abstract = {The nuclear factor-κB (NF-κB) is a DNA sequence-specific
regulator of many important biological processes, whose
activity is modulated by enzymatic acetylation. In one of
the best functionally characterized NF-κB complexes, the
p50/p65 heterodimer, acetylation of K221 at p65 causes a
decrease of DNA dissociation rate, whilst the acetylation of
K122 and K123, also at p65, markedly decreases the binding
affinity for DNA. By means of molecular dynamics simulations
based on the X-ray structure of the p50/p65 complex with
DNA, we provide insights on the structural determinants of
the acetylated complexes in aqueous solution. Lysine
acetylation involves the loss of favorable electrostatic
interactions between DNA and NF-κB, which is partially
compensated by the reduction of the desolvation free-energy
of the two binding partners. Acetylation at both positions
K122 and K123 is associated with a decrease of the
electrostatic potential at the p65/DNA interface, which is
only partially counterbalanced by an increase of the local
Na+ concentration. It induces the disruption of
base-specific and nonspecific interactions between DNA and
NF-κB and it is consistent with the observed decrease of
binding affinity. In contrast, acetylation at position K221
results in the loss of nonspecific protein–DNA
interactions, but the DNA recognition sites are not
affected. In addition, the loss of protein–DNA
interactions is likely to be counterbalanced by an increase
of the configurational entropy of the complex, which
provides, at a speculative level, a justification for the
observed decrease of NF-κB/DNA dissociation rate},
cin = {GRS / IAS-5},
ddc = {540},
cid = {I:(DE-Juel1)GRS-20100316 / I:(DE-Juel1)IAS-5-20120330},
pnm = {899 - ohne Topic (POF2-899)},
pid = {G:(DE-HGF)POF2-899},
typ = {PUB:(DE-HGF)16},
UT = {WOS:000303759000004},
doi = {10.1002/prot.24047},
url = {https://juser.fz-juelich.de/record/201298},
}