Base-Independent DNA Base-Excision Repair of 8-Oxoguanine.

Living organisms protect their genome from gene mutation by excising damaged DNA bases. Here, 8-oxoguanine (8OG) is one of the most abundant DNA lesions. In bacteria the base excision is catalyzed by the enzyme formamidopyrimidine-DNA- glycosylase (Fpg), for which two different orientations of 8OG binding into the active site of Fpg have been proposed: syn- and anti-conformation. Here, we present a new ribose-protonated repair mechanism for 8OG that is base-independent and can excise 8OG in both conformations. Using high-level QM/MM calculations with up to 588/573 atoms in the QM sphere, the activation barrier is computed in excellent agreement with the experimentally measured value. Since the excised base itself is not directly involved in the mechanism, this implies that lesion discrimination does not occur within the active site of the enzyme.

Oxidative Ring Contraction of Cyclobutenes: General Approach to Cyclopropylketones including Mechanistic Insights.

An original oxidative ring contraction of easily accessible cyclobutene derivatives for the selective formation of cyclopropylketones (CPKs) under atmospheric conditions is reported. Comprehensive mechanistic studies are proposed to support this novel, yet unusual, rearrangement. Insights into the mechanism ultimately led to simplification and generalization of the ring contraction of cyclobutenes using mCPBA as an oxidant. This unique and functional group tolerant transformation proceeds under mild conditions at room temperature, providing access to a new library of polyfunctionalized motifs. With CPKs being attractive and privileged pharmacophores, the elaboration of such a simple and straightforward strategy represents a highly valuable tool for drug discovery and medicinal chemistry. Additionally, the described method was employed to generate a pool of bioactive substances and key precursors in a minimum number of steps.

The Enzymatic Decarboxylation Mechanism of 5-Carboxy Uracil: A Comprehensive Quantum Chemical Study.

Dynamic regulation of DNA methylation is an important process for the control of gene expression in mammals. It is believed that in the demethylation pathway of 5-methyl cytosine, the intermediate 5-carboxy cytosine (5caC) can be actively decarboxylated alongside the substitution in the base excision repair. For the active decarboxylation of 5caC, a decarboxylase has not been identified so far. Due to the similar chemistry of the decarboxylation of 5-carboxy uracil (5caU) to uracil (U) in the pyrimidine salvage pathway catalyzed by the iso-orotate decarboxylase (IDCase), the study of this reaction might give valuable insights into the active 5caC decarboxylation process. In this work, we employ quantum chemical and molecular mechanic calculations and find that the catalytic mechanism of IDCase proceeds via a direct decarboxylation mechanism. Detailed investigations on the reaction coordinate reveal that it is a one-step mechanism with concerted proton transfer and C-C bond opening.

Range-Separated Density-Functional Theory in Combination with the Random Phase Approximation: An Accuracy Benchmark.

A formulation of range-separated random phase approximation (RPA) based on our efficient ω-CDGD-RI-RPA [J. Chem. Theory Comput. 2018, 14, 2505] method and a large scale benchmark study are presented. By application to the GMTKN55 data set, we obtain a comprehensive picture of the performance of range-separated RPA in general main group thermochemistry, kinetics, and noncovalent interactions. The results show that range-separated RPA performs stably over the broad range of molecular chemistry included in the GMTKN55 set. It improves significantly over semilocal DFT but it is still less accurate than modern dispersion corrected double-hybrid functionals. Furthermore, range-separated RPA shows a faster basis set convergence compared to standard full-range RPA making it a promising applicable approach with only one empirical parameter.