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Biomimetic hydrogen-bonding cascade for chemical activation: telling a nucleophile from a base.

ABSTRACT: Hydrogen bonding-assisted polarization is an effective strategy to promote bond-making and bond-breaking chemical reactions. Taking inspiration from the catalytic triad of serine protease active sites, we have devised a conformationally well-defined benzimidazole platform that can be systematically functionalized to install multiple hydrogen bonding donor (HBD) and acceptor (HBA) pairs in a serial fashion. We found that an increasing number of interdependent and mutually reinforcing HBD-HBA contacts facilitate the bond-forming reaction of a fluorescence-quenching aldehyde group with the cyanide ion, while suppressing the undesired Brønsted acid-base reaction. The most advanced system, evolved through iterative rule-finding studies, reacts rapidly and selectively with CN^- to produce a large (>180-fold) enhancement in the fluorescence intensity at λ _max = 450 nm.

SUBMITTER: Park H

PROVIDER: S-EPMC8178988 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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Biomimetic hydrogen-bonding cascade for chemical activation: telling a nucleophile from a base.

Park Hyunchang H Lee Dongwhan D

Chemical science 20201102 2

Hydrogen bonding-assisted polarization is an effective strategy to promote bond-making and bond-breaking chemical reactions. Taking inspiration from the catalytic triad of serine protease active sites, we have devised a conformationally well-defined benzimidazole platform that can be systematically functionalized to install multiple hydrogen bonding donor (HBD) and acceptor (HBA) pairs in a serial fashion. We found that an increasing number of interdependent and mutually reinforcing HBD-HBA cont ...[more]

PMID: 34163789

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Project description:We address the recent debate surrounding the ability of 2,4-difluorotoluene (F), a low-polarity mimic of thymine (T), to form a hydrogen-bonded complex with adenine in DNA. The hydrogen bonding ability of F has been characterized as small to zero in various experimental studies, and moderate to small in computational studies. However, recent X-ray crystallographic studies of difluorotoluene in DNA/RNA have indicated, based on interatomic distances, possible hydrogen bonding interactions between F and natural bases in nucleic acid duplexes and in a DNA polymerase active site. Since F is widely used to measure electrostatic contributions to pairing and replication, it is important to quantify the impact of this isostere on DNA stability. Here, we studied the pairing stability and selectivity of this compound and a closely related variant, dichlorotoluene deoxyriboside (L), in DNA, using both experimental and computational approaches. We measured the thermodynamics of duplex formation in three sequence contexts and with all possible pairing partners by thermal melting studies using the van't Hoff approach, and for selected cases by isothermal titration calorimetry (ITC). Experimental results showed that internal F-A pairing in DNA is destabilizing by 3.8 kcal/mol (van't Hoff, 37 °C) as compared with T-A pairing. At the end of a duplex, base-base interactions are considerably smaller; however, the net F-A interaction remains repulsive while T-A pairing is attractive. As for selectivity, F is found to be slightly selective for adenine over C, G, T by 0.5 kcal mol, as compared with thymine's selectivity of 2.4 kcal/mol. Interestingly, dichlorotoluene in DNA is slightly less destabilizing and slightly more selective than F, despite the lack of strongly electronegative fluorine atoms. Experimental data were complemented by computational results, evaluated at the M06-2X/6-31+G(d) and MP2/cc-pVTZ levels of theory. These computations suggest that the pairing energy of F to A is ~28% of that of T-A, and most of this interaction does not arise from the F···HN interaction, but rather from the CH···N interaction. The nucleobase analogue shows no inherent selectivity for adenine over other bases, and L-A pairing energies are slightly weaker than for F-A. Overall, the results are consistent with a small favorable noncovalent interaction of F with A offset by a large desolvation cost for the polar partner. We discuss the findings in light of recent structural studies and of DNA replication experiments involving these analogues.

Dataset Information

Biomimetic hydrogen-bonding cascade for chemical activation: telling a nucleophile from a base.

Publications

Biomimetic hydrogen-bonding cascade for chemical activation: telling a nucleophile from a base.

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