Journal Article

FZJ-2015-00152

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Molecular Recognition of Platinated DNA from Chromosomal HMGB1

Nguyen, T. H. ; Rossetti, G. (Corresponding Author)FZJ* ; Arnesano, F. ; Ippoliti, E.FZJ* ; Natile, G. ; Carloni, P.FZJ*

2014
American Chemical Society (ACS) Washington, DC

This record in other databases:      

Please use a persistent id in citations: doi:10.1021/ct500402e

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.

---

Contributing Institute(s):

1. Jülich Supercomputing Center (JSC)
2. Computational Biomedicine (IAS-5)
3. Computational Biomedicine (INM-9)

Research Program(s):

1. 411 - Computational Science and Mathematical Methods (POF2-411) (POF2-411)

Appears in the scientific report 2014

---

Database coverage:
; Current Contents - Physical, Chemical and Earth Sciences ; IF >= 5 ; JCR ; SCOPUS ; Science Citation Index ; Science Citation Index Expanded ; Thomson Reuters Master Journal List ; Web of Science Core Collection

---