Ultrafast fs coherent excitonic dynamics in CdSe quantum dots assemblies addressed and probed by 2D electronic spectroscopy.

We show in a joint experimental and theoretical study that ultrafast femto-second (fs) electronic coherences can be characterized in semi-conducting colloidal quantum dot (QD) assemblies at room temperature. The dynamics of the electronic response of ensembles of CdSe QDs in the solution and of QD dimers in the solid state is probed by a sequence of 3 fs laser pulses as in two-dimensional (2D) electronic spectroscopy. The quantum dynamics is computed using an excitonic model Hamiltonian based on the effective mass approximation. The Hamiltonian includes the Coulomb, spin-orbit, and crystal field interactions that give rise to the fine structure splittings. In the dimers studied, the interdot distance is sufficiently small to allow for an efficient interdot coupling and delocalization of the excitons over the two QDs of the dimer. To account for the inherent few percent size dispersion of colloidal QDs, the optical response is modeled by averaging over an ensemble of 2000 dimers. The size dispersion is responsible for an inhomogeneous broadening that limits the lifetimes of the excitonic coherences that can be probed to about 150 fs-200 fs. Simulations and experimental measurements in the solid state and in the solution demonstrate that during that time scale, a very rich electronic coherent dynamics takes place that involves several types of intradot and interdot (in the case of dimers) coherences. These electronic coherences exhibit a wide range of beating periods and provide a versatile basis for a quantum information processing device on a fs time scale at room temperature.

Quantum Device Emulates the Dynamics of Two Coupled Oscillators.

Our quantum device is a solid-state array of semiconducting quantum dots that is addressed and read by 2D electronic spectroscopy. The experimental ultrafast dynamics of the device is well simulated by solving the time-dependent Schrödinger equation for a Hamiltonian that describes the lower electronically excited states of the dots and three laser pulses. The time evolution induced in the electronic states of the quantum device is used to emulate the quite different nonequilibrium vibrational dynamics of a linear triatomic molecule. We simulate the energy transfer between the two local oscillators and, in a more elaborate application, the expectation values of the quantum mechanical creation and annihilation operators of each local oscillator. The simulation uses the electronic coherences engineered in the device upon interaction with a specific sequence of ultrafast pulses. The algorithm uses the algebraic description of the dynamics of the physical problem and of the hardware.

Massively parallel classical logic via coherent dynamics of an ensemble of quantum systems with dispersion in size.

Quantum parallelism can be implemented on a classical ensemble of discrete level quantum systems. The nanosystems are not quite identical, and the ensemble represents their individual variability. An underlying Lie algebraic theory is developed using the closure of the algebra to demonstrate the parallel information processing at the level of the ensemble. The ensemble is addressed by a sequence of laser pulses. In the Heisenberg picture of quantum dynamics the coherence between the N levels of a given quantum system can be handled as an observable. Thereby there are N2 logic variables per N level system. This is how massive parallelism is achieved in that there are N2 potential outputs for a quantum system of N levels. The use of an ensemble allows simultaneous reading of such outputs. Due to size dispersion the expectation values of the observables can differ somewhat from system to system. We show that for a moderate variability of the systems one can average the N2 expectation values over the ensemble while retaining closure and parallelism. This allows directly propagating in time the ensemble averaged values of the observables. Results of simulations of electronic excitonic dynamics in an ensemble of quantum dot (QD) dimers are presented. The QD size and interdot distance in the dimer are used to parametrize the Hamiltonian. The dimer N levels include local and charge transfer excitons within each dimer. The well-studied physics of semiconducting QDs suggests that the dimer coherences can be probed at room temperature.

Targeting G-quadruplexes with Organic Dyes: Chelerythrine-DNA Binding Elucidated by Combining Molecular Modeling and Optical Spectroscopy.

The DNA-binding of the natural benzophenanthridine alkaloid chelerythrine (CHE) has been assessed by combining molecular modeling and optical absorption spectroscopy. Specifically, both double-helical (B-DNA) and G-quadruplex sequences-representative of different topologies and possessing biological relevance, such as telomeric or regulatory sequences-have been considered. An original multiscale protocol, making use of molecular dynamics (MD) simulations and quantum mechanics/molecular mechanics (QM/MM) calculations, allowed us to compare the theoretical and experimental circular dichroism spectra of the different DNA topologies, readily providing atomic-level details of the CHE-DNA binding modes. The binding selectivity towards G-quadruplexes is confirmed by both experimental and theoretical determination of the binding free energies. Overall, our mixed computational and experimental approach is able to shed light on the interaction of small molecules with different DNA conformations. In particular, CHE may be seen as the building block of promising drug candidates specifically targeting G-quadruplexes for both antitumoral and antiviral purposes.

Induced Night Vision by Singlet-Oxygen-Mediated Activation of Rhodopsin.

In humans, vision is limited to a small fraction of the whole electromagnetic spectrum. One possible strategy for enhancing vision in deep-red or poor-light conditions consists of recruiting chlorophyll derivatives in the rod photoreceptor cells of the eye, as suggested in the case of some deep-sea fish. Here, we employ all-atom molecular simulations and high-level quantum chemistry calculations to rationalize how chlorin e6 (Ce6), widely used in photodynamic therapy although accompanied by enhanced visual sensitivity, mediates vision in the dark, shining light on a fascinating but largely unknown molecular mechanism. First, we identify persistent interaction sites between Ce6 and the extracellular loops of rhodopsin, the transmembrane photoreceptor protein responsible for the first steps in vision. Triggered by Ce6 deep-red light absorption, the retinal within rhodopsin can be isomerized thus starting the visual phototransduction cascade. Our data largely exclude previously hypothesized energy-transfer mechanisms while clearly lending credence to a retinal isomerization indirectly triggered by singlet oxygen, proposing an alternative mechanism to rationalize photosensitizer-mediated night vision.

Covalent Cross-Linking as an Enabler for Structural Mass Spectrometry.

The number of studies referring to the structural elucidation of intact biomolecular systems using mass spectrometry techniques has gradually increased in the post-2000s literature topics. As part of native mass spectrometry, this domain capitalizes on the kinetic trapping of physiological folds in view of probing solution-like conformational properties of isolated molecules or complexes after their electrospray transfer to the gas phase. Despite its efficiency for a wide array of analytes, this approach is expected to be pushed to its limits when considering highly dynamic systems or when dealing with nonideal operating conditions. To circumvent these limitations, we challenge the adequacy of an original strategy based on cross-linkers to improve the gas-phase stability of isolated proteins and ensure the preservation of folded conformations when measuring with strong transmission voltages, by spraying from denaturing solvents, or trapping for extended periods of time. Tested on cytochrome c, myoglobin, and ß-lactoglobulin cross-linked using BS3, we validated the process as structurally nonintrusive in solution using far-ultraviolet circular dichroism and unraveled the preservation of folded conformations showing better resilience to denaturation on cross-linked species using ion mobility. The resulting collision cross sections were found in agreement with the native fold, and a preservation of the proteins' secondary and tertiary structures was evidenced using molecular dynamics simulations. Our results provide new insights concerning the fate of electro-sprayed cross-linked conformers in the gas phase, while constituting promising evidence for the validation of this technique as part of future structural mass spectrometry workflows.

Charge-Transfer versus Charge-Separated Triplet Excited States of [ReI (dmp)(CO)3 (His124)(Trp122)]+ in Water and in Modified Pseudomonas aeruginosa Azurin Protein.

A computational investigation of the triplet excited states of a rhenium complex electronically coupled with a tryptophan side chain and bound to an azurin protein is presented. In particular, by using high-level molecular modeling, evidence is provided for how the electronic properties of the excited-state manifolds strongly depend on coupling with the environment. Indeed, only upon explicitly taking into account the protein environment can two stable triplet states of metal-to-ligand charge transfer or charge-separated nature be recovered. In addition, it is also demonstrated how the rhenium complex plus tryptophan system in an aqueous environment experiences too much flexibility, which prevents the two chromophores from being electronically coupled. This occurrence disables the formation of a charge-separated state. The successful strategy requires a multiscale approach of combining molecular dynamics and quantum chemistry. In this context, the strategy used to parameterize the force fields for the electronic triplet states of the metal complex is also presented.

Novel Molecular-Dynamics-Based Protocols for Phase Space Sampling in Complex Systems.

The adequate exploration of the phase space of a chromophore is a fundamental necessity for the simulation of their optical and photophysical properties, taking into account the effects of vibrational motion and, most importantly, the coupling with a (non-homogeneous) molecular environment. A representative set of conformational snapshots around the Franck-Condon region is also required to perform non-adiabatic molecular dynamics, for instance in the framework of surface hopping. Indeed, in the latter case one needs to prepare a set of initial conditions providing a meaningful and complete statistical base for the subsequent trajectory propagation. In this contribution, we propose two new protocols for molecular dynamics-based phase space sampling, called "local temperature adjustment" and "individual QM/MM-based relaxation." These protocols are intended for situations in which the popular Wigner distribution sampling procedure is not applicable-as it is the case when anharmonic or nonlinear vibrations are present-and where regular molecular dynamics sampling might suffer from an inaccurate distribution of internal energy or from inaccurate force fields. The new protocols are applied to the case of phase space sampling of [Re(CO)3(Im)(Phen)]+ (im, imidazole; phen, phenanthroline) in aqueous solution, showing the advantages and limitations of regular Wigner and molecular dynamics sampling as well as the strengths of the new protocols.

Dynamics of the excited-state hydrogen transfer in a (dG)·(dC) homopolymer: intrinsic photostability of DNA.

The intrinsic photostability of nucleic acids is intimately related to evolution of life, while its understanding at the molecular and electronic levels remains a challenge for modern science. Among the different decay pathways proposed in the last two decades, the excited-state hydrogen transfer between guanine-cytosine base pairs has been identified as an efficient non-reactive channel to dissipate the excess of energy provided by light absorption. The present work studies the dynamics of such phenomena taking place in a (dG)·(dC) B-DNA homopolymer in water solution using state-of-the-art molecular modelling and simulation methods. A dynamic effect that boosts the photostability of the inter-strand hydrogen atom transfers, inherent to the Watson-Crick base pairing, is unveiled and ascribed to the energy released during the proton transfer step. Our results also reveal a novel mechanism of DNA decay named four proton transfer (FPT), in which two protons of two adjacent G-C base pairs are transferred to form a biradical zwitterionic intermediate. Decay of the latter intermediate to the ground state triggers the transfer of the protons back to the guanine molecules recovering the Watson-Crick structure of the tetramer. This FPT process is activated by the close interaction of a nearby Na+ counterion with the oxygen atoms of the guanine nucleobases and hence represents a photostable channel operative in natural nucleic acids.

Absorption Spectroscopy and Photophysics of a ReI -dppz Probe for DNA-Mediated Charge Transport.

Optical properties of [Re(CO)3 (dppz)(py)]+ (dppz=dipyrido[3,2-a:2',3'-c]phenazine; py=pyridine) in acetonitrile, water and DNA have been investigated based on DFT, time-dependent-DFT (TD-DFT)/ conductor-like screening model, with and without explicit solvent molecules, and molecular dynamics. Whereas implicit solvent model is not appropriate to model optical properties of dppz-substituted metal complexes, adding explicit solvent molecules in interaction with dppz stabilizes the metal-to-ligand-charge-transfer (MLCT) transitions. Classical molecular dynamics simulations point to an important conformational flexibility, as evidenced by the coexistence of two conformers A and B. When considering the conformational sampling, the lowest band of the absorption spectrum is red-shifted and broadened up to 500 nm in agreement with the experimental spectra supporting important dynamical effects. The absorption spectra of [Re(CO)3 (dppz)(py-R)]+/ GC-DNA and [Re(CO)3 (dppz)(py-R)]+ /AT-DNA (R=CH2 -CH2 -COO- ) intercalated in both major or minor grooves exhibit a lowest energy charge separated (CS) band at about 600 nm and 500 nm, respectively, corresponding mainly to excitations from guanine and adenine to dppz. These states may play a central role into DNA-mediated charge transport processes. The over stabilization of the lowest 3 ILdppz state of [Re(CO)3 (dppz)(py)]+ in water as compared to acetonitrile could be responsible for the quenching of emission in water.

Steady-State Linear and Non-linear Optical Spectroscopy of Organic Chromophores and Bio-macromolecules.

Bio-macromolecules as DNA, lipid membranes and (poly)peptides are essential compounds at the core of biological systems. The development of techniques and methodologies for their characterization is therefore necessary and of utmost interest, even though difficulties can be experienced due to their intrinsic complex nature. Among these methods, spectroscopies, relying on optical properties are especially important to determine their macromolecular structures and behaviors, as well as the possible interactions and reactivity with external dyes-often drugs or pollutants-that can (photo)sensitize the bio-macromolecule leading to eventual chemical modifications, thus damages. In this review, we will focus on the theoretical simulation of electronic spectroscopies of bio-macromolecules, considering their secondary structure and including their interaction with different kind of (photo)sensitizers. Namely, absorption, emission and electronic circular dichroism (CD) spectra are calculated and compared with the available experimental data. Non-linear properties will be also taken into account by two-photon absorption, a highly promising technique (i) to enhance absorption in the red and infra-red windows and (ii) to enhance spatial resolution. Methodologically, the implications of using implicit and explicit solvent, coupled to quantum and thermal samplings of the phase space, will be addressed. Especially, hybrid quantum mechanics/molecular mechanics (QM/MM) methods are explored for a comparison with solely QM methods, in order to address the necessity to consider an accurate description of environmental effects on spectroscopic properties of biological systems.

Accurate Estimation of the Standard Binding Free Energy of Netropsin with DNA.

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.

Excited-states of a rhenium carbonyl diimine complex: solvation models, spin-orbit coupling, and vibrational sampling effects.

We present a quantum-chemical investigation of the excited states of the complex [Re(CO)3(Im)(Phen)]+ (Im = imidazole; Phen = 1,10-phenanthroline) in solution including spin-orbit couplings and vibrational sampling. To this aim, we implemented electrostatic embedding quantum mechanics/molecular mechanics (QM/MM) in the Amsterdam Density Functional program suite, suitable for time-dependent density functional calculations including spin-orbit couplings. The new implementation is employed to simulate the absorption spectrum of the complex, which is compared to the results of implicit continuum solvation and frozen-density embedding. Molecular dynamics simulations are used to sample the ground state conformations in solution. The results demonstrate that any study of the excited states of [Re(CO)3(Im)(Phen)]+ in solution and their dynamics should include extensive sampling of vibrational motion and spin-orbit couplings.

Deciphering the photosensitization mechanisms of hypericin towards biological membranes.

Resorting to state-of-the art molecular modeling and simulation techniques we provide full characterization of the photophysical properties of the naturally occurring hypericin chromophore, currently used in photodynamic therapy. In particular, we reveal the different photophysical pathways leading to intersystem-crossing and hence, triplet manifold population that is necessary for the subsequent production of singlet oxygen. In particular we identify an extended region of quasi-degeneracy between the first singlet excited state and three triplet state surfaces. This energetic factor allows the occurrence of intersystem-crossing even in the presence of a relatively small spin-orbit coupling. Furthermore, thanks to extended all-atom molecular dynamics simulations we provide insight into the interaction of hypericin with lipid bilayers. We demonstrate the formation of stable interactions with the membrane and, in particular, the penetration of hypericin into its hydrophobic core. This organization allows a spatial overlap between hypericin and the lipid oxidizable double bond pointing towards the production of singlet oxygen in close spatial proximity to its reactant, hence favoring photosensitization.

Ibuprofen and ketoprofen potentiate UVA-induced cell death by a photosensitization process.

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.

Photophysics of the Singlet Oxygen Sensor Green Chromophore: Self-Production of 1O2 Explained by Molecular Modeling.

We report a combined computational and experimental study to rationalize the behavior of a well-known singlet oxygen (1O2) probe, that is, the chromophore of the Singlet Oxygen Sensor Green: a fluoresceine-based sensor. In particular, we evidence that the presence of an intramoleculer charge transfer state that is no more present upon reaction with 1O2 explains the fluorescence enhancement observed in the presence of reactive oxygen species. Furthermore, we also unequivocally show the photophysical pathways leading to the fluorescence enhancement of fluoresceine upon irradiation with UVA lights and also in the absence of any oxygen activator. More specifically, we evidence that the presence of a possible intersystem crossing upon population of higher energy singlet electronic excited states will lead to the population of the fluoresceine triplet manifold and hence to the self-production of 1O2.

Simulating the Electronic Circular Dichroism Spectra of Photoreversible Peptide Conformations.

Electronic circular dichroism (CD) spectroscopy of peptides is one of the most important experimental characterization tools to get insights regarding their structure. Nevertheless, even though highly useful, the reliable simulations of CD spectra result in a complex task. Here, we propose a combination of quantum mechanics/molecular mechanics (QM/MM) methods with a semiempirical Hamiltonian based on the Frenkel excitons theory to efficiently describe the behavior of a model 27-amino acid α-helical peptide in water. Especially, we show how the choice of the QM region, including different possible hydrogen-bonding patterns, can substantially change the final CD spectrum shape. Moreover, we prove that our approach can correctly explain the changes observed in the peptide conformation (from α-helix to α-hairpin) when covalently linked to a protonated retinal-like molecular switch and exposing the system to UVA light, as previously observed by experiment and extensive molecular dynamics. Hence our protocol may be straightforwardly exploited to characterize light-induced conformation changes in photoactive materials and more generally protein folding processes.

Conformational polymorphism or structural invariance in DNA photoinduced lesions: implications for repair rates.

DNA photolesions constitute a particularly deleterious class of molecular defects responsible for the insurgence of a vast majority of skin malignant tumors. Dimerization of two adjacent thymines or cytosines mostly gives rise to cyclobutane pyrimidine dimers (CPD) and pyrimidine(6-4)pyrimidone 64-PP as the most common defects. We perform all-atom classical simulations, up to 2 µs, of CPD and 64-PP embedded in a 16-bp duplex, which reveal the constrasted behavior of the two lesions. In particular we evidence a very limited structural deformation induced by CPD while 64-PP is characterized by a complex structural polymorphism. Our simulations also allow to unify the contrasting experimental structural results obtained by nuclear magnetic resonance or Förster Resonant Energy Transfer method, showing that both low and high bent structures are indeed accessible. These contrasting behaviors can also explain repair resistance or the different replication obstruction, and hence the genotoxicity of these two photolesions.

Thermodynamics of DNA: sensitizer recognition. Characterizing binding motifs with all-atom simulations.

We report the investigation of the thermochemical properties of benzophenone interacting with B-DNA studied by all-atom molecular dynamic simulations. In particular, we determine the binding free energy for two competitive binding modes, minor groove binding and double insertion. Our results allow us to quantitatively resolve for the first time the mode of binding of this paradigmatic photosensitizer, indicating a marked preference for minor groove binding. Furthermore, we have settled a protocol allowing for the determination of binding energies in the case of non-covalent interaction with DNA, in particular, tackling the non-trivial problem of the strong reorganization of the DNA imposing extended statistical sampling. Our contribution paves the way to the systematic determination of the thermochemical properties of drugs or pollutants interacting with DNA.

Repair Rate of Clustered Abasic DNA Lesions by Human Endonuclease: Molecular Bases of Sequence Specificity.

In the present contribution, the interaction between damaged DNA and repair enzymes is examined by means of molecular dynamics simulations. More specifically, we consider clustered abasic DNA lesions processed by the primary human apurinic/apyrimidinic (AP) endonuclease, APE1. Our results show that, in stark contrast with the corresponding bacterial endonucleases, human APE1 imposes strong geometrical constraints on the DNA duplex. As a consequence, the level of recognition and, hence, the repair rate is higher. Important features that guide the DNA/protein interactions are the presence of an extended positively charged region and of a molecular tweezers that strongly constrains DNA. Our results are on very good agreement with the experimentally determined repair rate of clustered abasic lesions. The lack of repair for one particular arrangement of the two abasic sites is also explained considering the peculiar destabilizing interaction between the recognition region and the second lesion, resulting in a partial opening of the molecular tweezers and, thus, a less stable complex. This contribution cogently establishes the molecular bases for the recognition and repair of clustered DNA lesions by means of human endonucleases.