Challenges in simulating light-induced processes in DNA

© 2016 by the authors; licensee MDPI, Basel, Switzerland. In this contribution, we give a perspective on the main challenges in performing theoretical simulations of photoinduced phenomena within DNA and its molecular building blocks. We distinguish the different tasks that should be involved in the simulation of a complete DNA strand subject to UV irradiation: (i) stationary quantum chemical computations; (ii) the explicit description of the initial excitation of DNA with light; (iii) modeling the nonadiabatic excited state dynamics; (iv) simulation of the detected experimental observable; and (v) the subsequent analysis of the respective results. We succinctly describe the methods that are currently employed in each of these steps. While for each of them, there are different approaches with different degrees of accuracy, no feasible method exists to tackle all problems at once. Depending on the technique or combination of several ones, it can be problematic to describe the stacking of nucleobases, bond breaking and formation, quantum interferences and tunneling or even simply to characterize the involved wavefunctions. It is therefore argued that more method development and/or the combination of different techniques are urgently required. It is essential also to exercise these new developments in further studies on DNA and subsystems thereof, ideally comprising simulations of all of the different components that occur in the corresponding experiments

Molecular Dynamics Simulations of Binding Modes between Methylene Blue and DNA with Alternating GC and AT Sequences

The understanding of interactions between small molecules and DNA is crucial to design new anticancer drugs targeted to DNA. Methylene blue (MB) is a phenothiazinium dye that has shown promising results in photodynamic therapy treatment. The noncovalent binding of methylene blue to DNA was experimentally and theoretically analyzed in the past, but certain features of the binding mode are still not clear. In this work, force field molecular dynamics simulations were performed to simulate the binding of methylene blue to alternating GC and AT sequences at two different ionic strengths. External, intercalative, minor groove, and major groove binding modes are discussed based on energetic and structural analyses. External and major groove complexes were found to be unstable structures, although for poly­(dA-dT) the major groove binding mode cannot be discarded, especially at high ionic strengths. Minor groove and intercalative binding leads to stable adducts. The most energetically favorable orientation of the dye inside the minor groove is different for the two DNA sequences because of the different balances between the DNA deformation energy and the dye/DNA interaction energy. The intercalative binding is the most important interaction mode. The dye undergoes rotational transitions inside the intercalative pocket for both DNA sequences giving rise to three dye/DNA adducts that have different energetic and structural features. This rotational motion explains the different behavior found in experiments for the GC and AT nucleic acids at different ionic strengths

Electronic delocalization, charge transfer and hypochromism in the UV absorption spectrum of polyadenine unravelled by multiscale computations and quantitative wavefunction analysis

© 2017 The Royal Society of Chemistry. The characterization of the electronically excited states of DNA strands populated upon solar UV light absorption is essential to unveil light-induced DNA damage and repair processes. We report a comprehensive analysis of the electronic properties of the UV spectrum of single-stranded polyadenine based on theoretical calculations that include excitations over eight nucleobases of the DNA strand and environmental effects by a multiscale quantum mechanics/molecular mechanics scheme, conformational sampling by molecular dynamics, and a meaningful interpretation of the electronic structure by quantitative wavefunction analysis. We show that electronic excitations are extended mainly over two nucleobases with additional important contributions of monomer-like excitations and excitons delocalized over three monomers. Half of the spectral intensity derives from locally excited and Frenkel exciton states, while states with partial charge-transfer character account for the other half and pure charge-transfer states represent only a minor contribution. The hypochromism observed when going from the isolated monomer to the strand occurs independently from delocalization and charge transfer and is instead explained by long-range environmental perturbations of the monomer states

Electronic delocalization, charge transfer and hypochromism in the UV absorption spectrum of polyadenine unravelled by multiscale computations and quantitative wavefunction analysis

© 2017 The Royal Society of Chemistry. The characterization of the electronically excited states of DNA strands populated upon solar UV light absorption is essential to unveil light-induced DNA damage and repair processes. We report a comprehensive analysis of the electronic properties of the UV spectrum of single-stranded polyadenine based on theoretical calculations that include excitations over eight nucleobases of the DNA strand and environmental effects by a multiscale quantum mechanics/molecular mechanics scheme, conformational sampling by molecular dynamics, and a meaningful interpretation of the electronic structure by quantitative wavefunction analysis. We show that electronic excitations are extended mainly over two nucleobases with additional important contributions of monomer-like excitations and excitons delocalized over three monomers. Half of the spectral intensity derives from locally excited and Frenkel exciton states, while states with partial charge-transfer character account for the other half and pure charge-transfer states represent only a minor contribution. The hypochromism observed when going from the isolated monomer to the strand occurs independently from delocalization and charge transfer and is instead explained by long-range environmental perturbations of the monomer states

Quenching of Charge Transfer in Nitrobenzene Induced by Vibrational Motion

Although nitrobenzene is the smallest nitro-aromatic molecule, the nature of its electronic structure is still unclear. Most notably, the lowest-energy absorption band was assessed in numerous studies providing conflicting results regarding its charge-transfer character. In this study, we employ a combination of molecular dynamics and quantum chemical methods to disentangle the nature of the lowest-energy absorption band of nitrobenzene. Surprisingly, the charge-transfer transition from the benzene moiety to the nitro group is found to be quenched by a flow of charge into the opposite direction induced by vibrational motion. Beyond clarifying the charge-transfer character of nitrobenzene, we show that the widely used approach of analyzing the ground-state minimum-energy geometry provides completely wrong conclusions

Quenching of Charge Transfer in Nitrobenzene Induced by Vibrational Motion

Although nitrobenzene is the smallest nitro-aromatic molecule, the nature of its electronic structure is still unclear. Most notably, the lowest-energy absorption band was assessed in numerous studies providing conflicting results regarding its charge-transfer character. In this study, we employ a combination of molecular dynamics and quantum chemical methods to disentangle the nature of the lowest-energy absorption band of nitrobenzene. Surprisingly, the charge-transfer transition from the benzene moiety to the nitro group is found to be quenched by a flow of charge into the opposite direction induced by vibrational motion. Beyond clarifying the charge-transfer character of nitrobenzene, we show that the widely used approach of analyzing the ground-state minimum-energy geometry provides completely wrong conclusions

Exciton Localization on Ru-Based Photosensitizers Induced by Binding to Lipid Membranes

The characterization of electronic properties of metal complexes embedded in membrane environments is of paramount importance to develop efficient photosensitizers in optogenetic applications. Molecular dynamics and QM/MM simulations together with quantitative wave function analysis reveal a directional electronic redistribution of the exciton formed upon excitation of [Ru­(bpy)2(bpy-C17)]2+ when going from water to a lipid bilayer, despite the fact that the media influence neither the metal-to-ligand charge-transfer character nor the excitation energy of the absorption spectra. When the photosensitizer is embedded into the DOPC lipid membrane, exciton population is mainly located in the bypyridyl sites proximal to the positively charged surface of the bilayer due to electrostatic interactions. This behavior shows that the electronic structure of metal complexes can be controlled through the binding to external species, underscoring the crucial role of the environment in directing the electronic flow upon excitation and thus helping rational tuning of optogenetic agents

Cosolvent and Dynamic Effects in Binding Pocket Search by Docking Simulations

The lack of conformational sampling in virtual screening projects can lead to inefficient results because many of the potential drugs may not be able to bind to the target protein during the static docking simulations. Here, we performed ensemble docking for around 2000 United States Food and Drug Administration (FDA)-approved drugs with the RNA-dependent RNA polymerase (RdRp) protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) as a target. The representative protein structures were generated by clustering classical molecular dynamics trajectories, which were evolved using three solvent scenarios, namely, pure water, benzene/water and phenol/water mixtures. The introduction of dynamic effects in the theoretical model showed improvement in docking results in terms of the number of strong binders and binding sites in the protein. Some of the discovered pockets were found only for the cosolvent simulations, where the nonpolar probes induced local conformational changes in the protein that lead to the opening of transient pockets. In addition, the selection of the ligands based on a combination of the binding free energy and binding free energy gap between the best two poses for each ligand provided more suitable binders than the selection of ligands based solely on one of the criteria. The application of cosolvent molecular dynamics to enhance the sampling of the configurational space is expected to improve the efficacy of virtual screening campaigns of future drug discovery projects

Energy Transfer and Thermal Accommodation in Ozone Scattering from a Perfluorinated Self-Assembled Monolayer

A modification of the energy transfer model recently proposed by two of us (ref ) is tested in this work by an extensive comparison with the simulation results for O₃ scattering from a perfluorinated self-assembled monolayer (F-SAM) as well as with previous NO + FSAM and Ar + F-SAM scattering results. The model fits very well the trajectory data over a ∼10³-fold of incident energies. The percentage of energy transferred to the surface, predicted by the model at high incident energies, decreases with the number of degrees of freedom of the projectile because they compete with the surface degrees of freedom as possible destinations of the incident energy. The distributions of the scattered ozone molecules over translational and rotational states show a low-energy component characterized by a Maxwell–Boltzmann (MB) distribution at the surface temperature that survives at the highest collision energies. The dependence of the fraction of the MB component on the incident energy is an exponential decay function and the rate of decay is similar for the rotational and translational distributions. A non-negligible number of the O₃ + F-SAM trajectories that penetrate the surface at high energies have very long residence times (longer than the simulation time), which enables thermal accommodation of the rotational and translational degrees of freedom. A new method to categorize the O₃ + F-SAM trajectories, based on the residence time, shows that, at very low incident energies (<10 kcal/mol), thermal accommodation can be achieved in a single collision event

Cyclobutane Thymine Photodimerization Mechanism Revealed by Nonadiabatic Molecular Dynamics

The formation of cyclobutane thymine dimers is one of the most important DNA carcinogenic photolesions induced by ultraviolet irradiation. The long debated question whether thymine dimerization after direct light excitation involves singlet or triplet states is investigated here for the first time using nonadiabatic molecular dynamics simulations. We find that the precursor of this [2 + 2] cycloaddition reaction is the singlet doubly π²π*² excited state, which is spectroscopically rather dark. Excitation to the bright ¹ππ* or dark ¹nπ* excited states does not lead to thymine dimer formation. In all cases, intersystem crossing to the triplet states is not observed during the simulated time, indicating that ultrafast dimerization occurs in the singlet manifold. The dynamics simulations also show that dimerization takes place only when conformational control happens in the doubly excited state