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Spatial and Temporal Resolution of the Oxygen-Independent Photoinduced DNA Interstrand Cross-Linking by a Nitroimidazole Derivative.

ABSTRACT: DNA damage is ubiquitous in nature and is at the basis of emergent treatments such as photodynamic therapy, which is based on the activation of highly oxidative reactive oxygen species by photosensitizing O₂. However, hypoxia observed in solid tumors imposes the necessity to devise oxygen-independent modes of action able to induce DNA damage under a low oxygen concentration. The complexity of these DNA damage mechanisms in realistic environments grows exponentially when taking into account light absorption and subsequent excited-state population, photochemical and (photo)-redox reactions, the multiple species involved in different electronic states, noncovalent interactions, multiple reaction steps, and the large number of DNA reactive sites. This work tackles all the intricate reactivity of a photosensitizer based on a nitroimidazole derivative reacting toward DNA in solution under UV light exposition. This is performed through a combination of ground- and excited-state quantum chemistry, classical molecular dynamics, and hybrid QM/MM simulations to rationalize in detail the formation of DNA interstrand cross-links (ICLs) exerted by the noncanonical noncovalent photosensitizer. Unprecedented spatial and temporal resolution of these phenomena is achieved, revealing that the ICL is sequence-specific and that the fastest reactions take place at AT, GC, and GT steps involving either the opposite nucleobases or adjacent Watson-Crick base pairs. The N7 and O6 positions of guanine, the N7 and N3 sites of adenine, the N4 position of cytosine, and the O2 atom of thymine are deemed as the most nucleophile sites and are positively identified to participate in the ICL productions. This work provides a multiscale computational protocol to study DNA reactivity with noncovalent photosensitizers, and contributes to the understanding of therapies based on photoinduced DNA damage at molecular and electronic levels. In addition, we believe the depth understanding of these processes should assist the design of new photosensitizers considering their molecular size, electronic properties, and the observed regioselectivity toward nucleic acids.

SUBMITTER: Abdelgawwad AMA

PROVIDER: S-EPMC9277591 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Most studies on the biological effects of future climatic changes rely on seasonally aggregated, coarse-resolution data. Such data mask spatial and temporal variability in microclimate driven by terrain, wind and vegetation, and ultimately bear little resemblance to the conditions that organisms experience in the wild. Here, I present the methods for providing fine-grained, hourly and daily estimates of current and future temperature and soil moisture over decadal timescales. Observed climate data and spatially coherent probabilistic projections of daily future weather were disaggregated to hourly and used to drive empirically calibrated physical models of thermal and hydrological microclimates. Mesoclimatic effects (cold-air drainage, coastal exposure and elevation) were determined from the coarse-resolution climate surfaces using thin-plate spline models with coastal exposure and elevation as predictors. Differences between micro and mesoclimate temperatures were determined from terrain, vegetation and ground properties using energy balance equations. Soil moisture was computed in a thin upper layer and an underlying deeper layer, and the exchange of water between these layers was calculated using the van Genuchten equation. Code for processing the data and running the models is provided as a series of R packages. The methods were applied to the Lizard Peninsula, United Kingdom, to provide hourly estimates of temperature (100 m grid resolution over entire area, 1 m for a selected area) for the periods 1983-2017 and 2041-2049. Results indicated that there is a fine-resolution variability in climatic changes, driven primarily by interactions between landscape features and decadal trends in weather conditions. High-temporal resolution extremes in conditions under future climate change were predicted to be considerably less novel than the extremes estimated using seasonally aggregated variables. The study highlights the need to more accurately estimate the future climatic conditions experienced by organisms and equips biologists with the means to do so.

Dataset Information

Spatial and Temporal Resolution of the Oxygen-Independent Photoinduced DNA Interstrand Cross-Linking by a Nitroimidazole Derivative.

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