Orbital interactions and charge redistribution in weak hydrogen bonds: Watson–Crick GC mimic involving CH proton donor and F proton acceptor groups

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AbstractThe discovery by Kool and coworkers that 2,4‐difluorotoluene (F) mimics thymine (T) in DNA replication has led to controversy regarding the question of whether this mimic has the capability of forming hydrogen bonds with adenine (A). Recently, we have provided evidence for an important role of both hydrogen bonding and steric effects in the replication of DNA. In the present work, we extend our study to mimics (GFC′N′ and CN′NF) of the bases guanine (G) and cytosine (C). We address not only the question of the strengths of the hydrogen bonds in GFC′N′CN′NF as compared with those in GC but we focus in particular on the nature of these interactions. Thus, we have analyzed GFC′N′CN′NF and GC at the BP86/TZ2P level of density functional theory (DFT). In line with previous experience, this approach is shown to achieve close agreement with the available data from ab initio computations and experiment: the complexation energy of GFC′N′CN′NF (‐4.1 kcal/mol) is confirmed to be much weaker indeed than that of GC (‐26.1 kcal/mol). Interestingly, the weak hydrogen bonds in GFC′N′CN′NF still poses a significant orbital interaction component that resembles the situation for the more strongly bound GC, as follows from (1) an analysis of the orbital electronic structure of GFC′N′CN′NF and GC, (2) a quantitative decomposition of the GFC′N′CN′NF and GC bond energies, as well as (3) a quantitative decomposition of the charge redistribution associated with the GFC′N′ CN′NF and GC interactions based on the Voronoi deformation density (VDD) method. The VDD method allows us to decompose the charge redistribution ΔQ per atom into a component associated with the Pauli repulsive orbital interactions and a component associated with the bonding orbital interactions: ΔQ = ΔQPauli + ΔQoi. Implications of our findings for the mechanism of DNA replication are discussed. © 2006 Wiley Periodicals, Inc. Int J Quantum Chem, 2006