TY  - JOUR
AU  - Nguyen, Trung Hai
AU  - Rossetti, Giulia
AU  - Arnesano, Fabio
AU  - Ippoliti, Emiliano
AU  - Natile, Giovanni
AU  - Carloni, Paolo
TI  - Molecular Recognition of Platinated DNA from Chromosomal HMGB1
JO  - Journal of chemical theory and computation
VL  - 10
IS  - 8
SN  - 1549-9626
CY  - Washington, DC
PB  - American Chemical Society (ACS)
M1  - FZJ-2015-00152
SP  - 3578 - 3584
PY  - 2014
AB  - 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.
LB  - PUB:(DE-HGF)16
UR  - <Go to ISI:>//WOS:000340351200068
C6  - pmid:26588321
DO  - DOI:10.1021/ct500402e
UR  - https://juser.fz-juelich.de/record/186051
ER  -