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000186051 1001_ $$0P:(DE-HGF)0$$aNguyen, Trung Hai$$b0
000186051 245__ $$aMolecular Recognition of Platinated DNA from Chromosomal HMGB1
000186051 260__ $$aWashington, DC$$bAmerican Chemical Society (ACS)$$c2014
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000186051 520__ $$aCisplatin 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.
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000186051 7001_ $$0P:(DE-Juel1)145921$$aRossetti, Giulia$$b1$$eCorresponding Author$$ufzj
000186051 7001_ $$0P:(DE-HGF)0$$aArnesano, Fabio$$b2
000186051 7001_ $$0P:(DE-Juel1)146009$$aIppoliti, Emiliano$$b3$$ufzj
000186051 7001_ $$0P:(DE-HGF)0$$aNatile, Giovanni$$b4
000186051 7001_ $$0P:(DE-Juel1)145614$$aCarloni, Paolo$$b5$$ufzj
000186051 773__ $$0PERI:(DE-600)2166976-4$$a10.1021/ct500402e$$gVol. 10, no. 8, p. 3578 - 3584$$n8$$p3578 - 3584$$tJournal of chemical theory and computation$$v10$$x1549-9626$$y2014
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