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@ARTICLE{Nguyen:186051,
author = {Nguyen, Trung Hai and Rossetti, Giulia and Arnesano, Fabio
and Ippoliti, Emiliano and Natile, Giovanni and Carloni,
Paolo},
title = {{M}olecular {R}ecognition of {P}latinated {DNA} from
{C}hromosomal {HMGB}1},
journal = {Journal of chemical theory and computation},
volume = {10},
number = {8},
issn = {1549-9626},
address = {Washington, DC},
publisher = {American Chemical Society (ACS)},
reportid = {FZJ-2015-00152},
pages = {3578 - 3584},
year = {2014},
abstract = {Cisplatin cures testicular and ovarian cancers with
unprecedented potency. It induces its beneficial activity by
covalently binding to DNA. Repair enzymes, which remove the
platinated lesions from DNA, cause drug resistance.
Chromosomal High Mobility Group Box proteins (HMGB) may
interfere with this process by binding to platinated DNA.
Using 8 μs multiple-walker well-tempered metadynamics
simulations, here, we investigated the structural and the
energetic determinants of one of the HMGB proteins (HMGB1A)
in complex with the platinated oligonucleotide
[Pt(NH3)2]2+-d(CCUCTCTG*G*ACCTTCC)-d(GGAGAGACCTGGAAGG) (*G
are platinated guanines), for which experimental structural
information is available. The calculated affinity is in good
agreement with experiment. The process is predicted to be
enthalpy-driven, as found for other protein/DNA complexes.
The Lys7 residue, whose side-chain was not resolved in the
X-ray structure, is found to interact with the C4
5′-phosphate and this interaction emerges as a key facet
for the molecular recognition process. In addition, our
calculations provide a molecular basis for the
experimentally measured decreased affinity of HMGB1A for
platinated DNA, as a consequence of Cys22-Cys44 S–S bridge
formation (such an oxidation cannot take place in some
members of this protein family present in the testis, where
the drug is particularly effective). This decrease is likely
to be caused by a small yet significant rearrangement of
helices H1 and H2 with consequent alteration of the Phe37
juxtaposition.},
cin = {JSC / IAS-5 / INM-9},
ddc = {540},
cid = {I:(DE-Juel1)JSC-20090406 / I:(DE-Juel1)IAS-5-20120330 /
I:(DE-Juel1)INM-9-20140121},
pnm = {411 - Computational Science and Mathematical Methods
(POF2-411)},
pid = {G:(DE-HGF)POF2-411},
typ = {PUB:(DE-HGF)16},
UT = {WOS:000340351200068},
pubmed = {pmid:26588321},
doi = {10.1021/ct500402e},
url = {https://juser.fz-juelich.de/record/186051},
}