Theoretical study on the stability of N-glycosyl bonds: why does N7-platination not promote depurination?
The depurination reaction of guanosine, protonated or modified with cisplatin at the N7 position, has been studied by density functional theory (DFT), coupled with a continuum treatment of solvation. Protonation accelerates the depurination reaction whereas N7-platination, the initial product of cisplatin binding to DNA, does not. The computed reaction energy profiles demonstrate that N7-platination has only a minor effect on the energetics of the transition state, whereas protonation lowers it by approximately 10 kcal mol(-1). The orbitals involved in N7-Pt/H bonding are examined, and electronic differences between the two substituted guanines are identified. Natural bond orbital analysis, fragment orbital analysis, and extended transition-state theory reveal how the electronically different substituents at the N7 position control the stability of the N9-C1' bond. The detailed description of the electronic structure of the N7-substituted guanosines and the computational protocol developed to obtain a realistic model for these systems not only explain a longstanding enigma but also provide guidelines for further studies toward understanding the interactions of cisplatin with DNA.
Baik
Mu-Hyun
MH
Department of Chemistry, Columbia University, New York, New York 10027, USA.
Friesner
Richard A
RA
Lippard
Stephen J
SJ
D002945:Cisplatin / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D004247:DNA / Q000737:chemistry* / Q000187:drug effects / Q000378:metabolism; D018736:DNA Adducts / Q000737:chemistry / Q000378:metabolism; D003849:Deoxyguanosine / Q000737:chemistry / Q000378:metabolism; D006031:Glycosylation; D006151:Guanosine / Q000737:chemistry* / Q000378:metabolism; D008958:Models, Molecular; D009584:Nitrogen / Q000737:chemistry / Q000378:metabolism; D010984:Platinum / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D013816:Thermodynamics
D018736:DNA Adducts; C057270:cisplatin-DNA adduct; D006151:Guanosine; D010984:Platinum; D004247:DNA; D003849:Deoxyguanosine; D009584:Nitrogen; D002945:Cisplatin