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Oxidatively generated lesions such as 8-oxo-7, 8-dihydroguanine (8-oxoG) on RNA strands constitute a hallmark marker of the oxidative stress in the cell. Poly-C binding protein 1 (PCBP1) is able to specifically recognize severely damaged RNA strands containing two 8-oxoG lesions separated by five nucleobases, which trigger a signaling pathway leading to cell apoptosis. We apply an in silico protocol based on microsecond timescale all-atom classical molecular dynamics simulations associated with conformational and energy analyses to unveil the specific recognition mechanism at a molecular level. By comparing the RNA and protein behavior for sequences with six different damage profiles, our results highlight an allosteric mechanism, allowing a stronger binding of the oxidized guanine at position 9 only if another 8-oxoG lesion is present at position 15, in full agreement with experiments. We assess the role of lysine K23 and the additional ketone group of the oxidized guanine, thanks to computational site-directed mutagenesis.

The combination of several closely spaced DNA lesions, which can be induced by a single radical hit, constitutes a hallmark in the DNA damage landscape and radiation chemistry. The occurrence of such a tandem base lesion gives rise to a strong coupling with the double helix degrees of freedom and induces important structural deformations, in contrast to DNA strands containing a single oxidized nucleobase. Although such complex lesions are known to be refractory to repair by DNA glycosylases, there is still a lack of structural evidence to rationalize these phenomena. In this contribution, we explore, by numerical modeling and molecular simulations, the behavior of the bacterial glycosylase responsible for base excision repair (MutM), specialized in excising oxidatively-damaged defects such as 7,8-dihydro-8-oxoguanine (8-oxoG). The difference in lesion recognition between a simple damage and a tandem lesion featuring an additional abasic site is assessed at atomistic resolution owing to microsecond molecular dynamics simulations and machine learning postprocessing, allowing to extensively pinpoint crucial differences in the interaction patterns of the damaged bases. Our results reveal substantial changes in the interaction network surrounding the 8-oxoG upon addition of an adjacent abasic site, leading to the perturbation of the intercalation triad which is crucial for lesion recognition and processing. The recognition process might also be impacted by a more constrained MutM-DNA binding upon tandem damage, as shown by the machine learning post-processing. This work advocates for the use of such high throughput numerical simulations for exploring the complex combinatorial chemistry of tandem DNA lesions repair and more generally local multiple damaged sites of the utmost significance in radiation chemistry.

The 8-oxo-7,8-dihydroguanine, referred to as 8-oxoG, is a highly mutagenic DNA lesion that can provoke the appearance of mismatches if it escapes the DNA Damage Response. The specific recognition of its structural signature by the hOGG1 glycosylase is the first step along the Base Excision Repair pathway, which ensures the integrity of the genome by preventing the emergence of mutations. 8-oxoG formation, structural features, and repair have been matters of extensive research; more recently, this active field of research expended to the more complicated case of 8-oxoG within clustered lesions. Indeed, the presence of a second lesion within 1 or 2 helix turns can dramatically impact the repair yields of 8-oxoG by glycosylases. In this work, we use μs-range molecular dynamics simulations and machine-learning-based postanalysis to explore the molecular mechanisms associated with the recognition of 8-oxoG by hOGG1 when embedded in a multiple-lesion site with a mismatch in 5′ or 3′. We delineate the stiffening of the DNA–protein interactions upon the presence of the mismatches, and rationalize the much lower repair yields reported with a 5′ mismatch by describing the perturbation of 8-oxoG structural features upon addition of an adjacent lesion.

Abstract Nonsteroidal 2-arylproprionic acids are widely used, over-the-counter, anti-inflammatory drugs. Photosensitivity is a commonly overlooked adverse effect of these drugs. Based on the combined use of cell viability assays and molecular modeling, we prove and rationalize the photochemical pathways triggering photosensitization for two drugs, ibuprofen and ketoprofen. As its parent compound benzophenone, ketoprofen produces singlet oxygen, upon triplet manifold population. However, ibuprofen and ketoprofen photodissociate and hence may generate two highly reactive radicals. The formation of metastable aggregates between the two drugs and B-DNA is also directly probed by molecular dynamics. Our approach characterizes the coupled influence of the drug’s intrinsic photochemistry and the interaction pattern with DNA. The photosensitization activity of nonsteroidal 2-arylproprionic acids, being added to gels and creams for topical use, should be crucially analyzed and rationalized to enact the proper preventive measures.

DNA is the target of chemical compounds (drugs, pollutants, photosensitizers, etc.), which bind through non-covalent interactions. Depending on their structure and their chemical properties, DNA binders can associate to the minor or to the major groove of double-stranded DNA. They can also intercalate between two adjacent base pairs, or even replace one or two base pairs within the DNA double helix. The subsequent biological effects are strongly dependent on the architecture of the binding motif. Discriminating between the different binding patterns is of paramount importance to predict and rationalize the effect of a given compound on DNA. The structural characterization of DNA complexes remains, however, cumbersome at the experimental level. In this contribution, we employed all-atom molecular dynamics simulations to determine the standard binding free energy of DNA with netropsin, a well-characterized antiviral and antimicrobial drug, which associates to the minor groove of double-stranded DNA. To overcome the sampling limitations of classical molecular dynamics simulations, which cannot capture the large change in configurational entropy that accompanies binding, we resort to a series of potentials of mean force calculations involving a set of geometrical restraints acting on collective variables.

Pure inductive effects on the gas-phase basicity of seven benzene derivatives (3- and 4-substitution) are monitored in a continuous way using fictitious hydrogen atoms bearing an adjustable nuclear charge Z*. This approach (H* method) affords three main advantages over existing treatments: such entities are by definition purely inductive (without any underlying assumptions), use of empirical parameters is circumvented, and yet the method has been designed to remain particularly easy to use. We directly establish the linear dependence of proton affinities on inductive effects and, more quantitatively, measure accurate sensitivities ρI* analogous to Taft’s coefficients. Functional centers exhibit contrasted values, up to a factor of 3, which finds an interpretation within the framework of the HSAB theory. The sensitivities ρI* for 3- and 4-substitution are quantified. The associated para/meta ρI* ratio ranges from 1.02 to 1.16 according to the functional center. These values, always slightly superior to unity, denote a contribution of π electrons in the transmission of the inductive effect. This effect, first identified by Exner, is shown to account for ca. 30% of the basicity of benzoic acid, which is taken as an example. [ABSTRACT FROM AUTHOR]