Measurement and prediction of quantum coherence effects in biological processes

This themed issue presents a collection of articles on the measurement and prediction of quantum coherence effects in biological processes.</p

QM/MM Study of L-Lactate Oxidation by Flavocytochrome b2

In this work, we have performed molecular dynamics simulations using a hybrid Quantum Mechanics/Molecular Mechanics (QM/MM) scheme to study the mechanism of L-lactate oxidation by flavocytochrome b2 (Fcb2). Our results obtained at the QM(AM1)/MM level have been improved by single-point corrections using density functional theory (DFT) methods. Free energy surfaces have been calculated in the framework of the hydride transfer hypothesis. This mechanism involves the transfer of the lactate hydroxyl proton to H373 while the substrate αH atom is transferred as a hydride to the flavin mononucleotide (FMN) prosthetic group anchored in the active site. Four different systems have been modeled: wild-type enzyme considering R289 in a distal or a proximal conformation observed in crystal structures and the D282N and Y254L variants (with R289 in a distal position). Simulation results highlight the influence of the environment on the catalytic mechanism by describing a step-wise process in the WT enzyme with R289 in a distal position and a concerted mechanism for the other systems. In the step-wise mechanism, the hydride transfer to flavin can occur only after a proton transfer from substrate to H373. Modifications of the electrostatic field around L-lactate or H373 disfavor the highly charged complex resulting from this proton transfer. Simulations of the Y254L variant also reveal some effect of steric changes

Singlet-triplet gaps in large multireference systems: spin-flip-driven alternatives for bioinorganic modelling

The proper description of low-spin states of open-shell systems, which are commonly encountered in the field of bioinorganic chemistry, rigorously requires using multireference ab initio methodologies. Such approaches are unfortunately very CPU-time consuming as dynamic correlation effects also have to be taken into account. The broken-symmetry unrestricted (spin-polarized) density functional theory (DFT) technique has been widely employed up to now to bypass that drawback, but despite a number of relative successes in the determination of singlet-triplet gaps, this framework cannot be considered as entirely satisfactory. In this contribution, we investigate some alternative ways relying on the spin-flip time-dependent DFT approach [Y. Shao et al. J. Chem. Phys. 118, 4807 (2003)]. Taking a few well-documented copper-dioxygen adducts as examples, we show that spin-flip (SF)-DFT computed singlet-triplet gaps compare very favorably to either experimental results or large-scale CASMP2 computations. Moreover, it is shown that this approach can be used to optimize geometries at a DFT level including some multireference effects. Finally, a clear-cut added value of the SF-DFT computations is drawn: if pure ab initio data are required, then the electronic excitations revealed by SF-DFT can be considered in designing dramatically reduced zeroth-order variational spaces to be used in subsequent multireference configuration interaction or multireference perturbation treatments

Quantum effects in ultrafast electron transfers in cytochrome

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MODELISATION MULTIECHELLE DE MONOOXYGENASES A CENTRES CUIVREUX NON COUPLES :de l'activation du dioxygène au transfert électronique à longue distance.

Non-coupled monooxygenase such as PHM and DβM catalyze the stereospecific hydroxylation of various substrates by insertion of one oxygen atom into a C — H bond. They contain two cuprous centers separated by a solvent cleft, which both contribute to the four electron reduction of dioxygen during the catalytic cycle. In spite of huge experimental and theoretical efforts, several key steps of the mechanism remain obscure, especially from a molecular point of view. In this contribution we employ various theoretical methodologies, ranging from gas phase ab initio calculations to hybrid DFT/MM approaches, to address successively three of the main steps of this mechanism. We show that dioxygen activation at the cuprous Cu M active site is achieved through a singlet η2 side-on coordination. This copper/superoxo adduct is able to catalyze the rupture of the substrate C — H bond with an acceptable activation energy for a biochemical event. The electronic description of the reaction reveals an hydride transfer and the release of an intermediate carbocationic substrate. It is suggested that the intervention of one electron from the CuH active site at this step allow to complete the reaction and to obtain the hydroxylated substrate. Then, this long range electron transfer step is studied by mean of Molecular Dynamics Simulations on the entire PHM enzyme. Our simulations lead to propose a simple electron pathway in which the role of the Gln 170 residue is highlighted. The results are in fair agreement with experimental trends. The adduct is able to catalyze the rupture of the substrate C — H bond with an acceptable activation energy for a biochemical event. The electronic description of the reaction reveals an hydride transfer and the release of an intermediate carbocationic substrate. It is suggested hat the intervention of one electron from the CuH active site at this step allow to complete the reaction and to obtain the hydroxylated substrate. Then, this long range electron transfer step is studied by mean of Molecular Dynamics Simulations on the entire PHM enzyme. Our simulations lead to propose a simple electron pathway in which the role of the Gln 170 residue is highlighted. The results are in fair agreement with experimental trends.Les monooxygénases à centres cuivreux non couplés catalysent l’hydroxylation stéréospécifique de substrats par insertion d’un atome d’oxygène dans une liaison C — H. Elles contiennent deux centres cuivreux, CuM et CuH séparés, d'une distance de 11 Å par une poche de solvant, lesquels fournissent chacun un électron durant le cycle catalytique qui voit la réduction complète d'une molécule de dioxygène. Malgré de nombreux efforts expérimentaux et théoriques, la description au niveau moléculaire du mécanisme réactionnel reste lacunaire. Dans ce travail nous employons diverses approches de chimie théorique pour modéliser les étapes successives du mécanisme de ces enzymes en nous appuyant principalement sur les données expérimentales issues d'études biomimétiques. Grâce à l'utilisation de méthodes ab initio multiréférences adaptées, nous montrons que l'activation du dioxygène sur le centre cuivreux CuM est obtenue par une coordination de type eta 2 side-on dans un état de spin singulet. Cet adduit permet ensuite de transférer l'atome d'hydrogène de la liaison C — H du substrat sous forme d'hydrure. A l'issue de cette deuxième étape, il est suggéré que l'apport du second électron à partir du centre CuH permet de compléter le cycle catalytique et de former le substrat hydroxylé attendu. Une étude de Dynamique Moléculaire couplée au calcul des paramètres de la théorie de Marcus montre enfin que ce transfert électronique à longue distance est envisageable via une molécule d’eau dont la position pontante stabilisée par le résidu Gln170 assure la connection entre les deux centres actifs

Femtosecond responses of hydrated DNA irradiated by ionizing rays focus on the sugar-phosphate part

International audienceIn this article, we investigate the mechanisms of DNA ionization upon irradiation by 0.5 meV alpha particles. We focus on the sugar-phosphate group and its hydration shell. In radiation chemistry, the term quasi-direct effect refers the physical and chemical responses taking place after irradiation of solvent molecules pertaining to the solvation shells of solutes. The molecular mechanisms accounting for the quasi-direct effect are actually largely elusive, especially for those prevailing in the early timescales (< 10–12 s). We report Real-Time Time-Dependent Auxiliary Density Functional Theory simulations carried out within the framework of hybrid QM/MM scheme (Quantum Mechanics/Molecular Mechanics) with polarizable and non-polarizable embedding. Ten water molecules from the solvation shell of DNA backbone are independently irradiated. We find that during the first femtoseconds after irradiation, the holes formed on the irradiated water remain at their sites of formation. Electrostatic induction within the environment does not significantly impact charge migrations. We address the hypothesis that charge migration driven by electron correlation is responsible for an ultrafast H2O+ to DNA charge transfers, which would account for a quasi-direct effect. We find that pure charge migration at fixed nuclear positions is not responsible for the quasi-direct effect when considering sugar-phosphate solvation shells

On the role of charge transfer in many-body non-covalent interactions

Charge transfer is one of the mechanisms involved in non-covalent interactions. In molecular dimers, its contribution to pairwise interaction energies has been studied extensively using a variety of interaction energy decomposition schemes. In polar interactions such as hydrogen bonds, it can contribute ten or several tens of percent of the interaction energy. Less is known about its importance in higher-order interactions in many-body systems, mainly because of the lack of methods applicable to this problem. In this work, we extend our method for the quantification of the charge-transfer energy based on constrained DFT to many-body cases and apply it to model trimers extracted from molecular crystals. Our calculations show that charge transfer can account for a large fraction of the total three-body interaction energy. This also has implications for DFT calculations of many-body interactions in general as it is known that many DFT functionals struggle to describe charge-transfer effects correctly

First-Principles Simulations of Biological Molecules Subjected to Ionizing Radiation

International audienceIonizing rays cause damage to genomes, proteins, and signaling pathways that normally regulate cell activity, with harmful consequences such as accelerated aging, tumors, and cancers but also with beneficial effects in the context of radiotherapies. While the great pace of research in the twentieth century led to the identification of the molecular mechanisms for chemical lesions on the building blocks of biomacromolecules, the last two decades have brought renewed questions, for example, regarding the formation of clustered damage or the rich chemistry involving the secondary electrons produced by radiolysis. Radiation chemistry is now meeting attosecond science, providing extraordinary opportunities to unravel the very first stages of biological matter radiolysis. This review provides an overview of the recent progress made in this direction, focusing mainly on the atto- to femto- to picosecond timescales. We review promising applications of time-dependent density functional theory in this context

Modélisation multiéchelle de monooxygénases à centres cuivreux non couplés (de l'activation du dioxygène au transfert électronique à longue distance)

Les monooxygénases à centres cuivreux non couplés catalysent l hydroxylation stéréospécifique de substrats par insertion d un atome d oxygène dans une liaison C H. Elles contiennent deux centres cuivreux, CuM et CuH séparés, d'une distance de 11 Å par une poche de solvant, lesquels fournissent chacun un électron durant le cycle catalytique qui voit la réduction complète d'une molécule de dioxygène. Malgré de nombreux efforts expérimentaux et théoriques, la description au niveau moléculaire du mécanisme réactionnel reste lacunaire. Dans ce travail nous employons diverses approches de chimie théorique pour modéliser les étapes successives du mécanisme de ces enzymes en nous appuyant principalement sur les données expérimentales issues d'études biomimétiques. Grâce à l'utilisation de méthodes ab initio multiréférences adaptées, nous montrons que l'activation du dioxygène sur le centre cuivreux CuM est obtenue par une coordination de type 2 side-on dans un état de spin singulet. Cet adduit permet ensuite de transférer l'atome d'hydrogène de la liaison C H du substrat sous forme d'hydrure. A l'issue de cette deuxième étape, il est suggéré que l'apport du second électron à partir du centre CuH permet de compléter le cycle catalytique et de former le substrat hydroxylé attendu. Une étude de Dynamique Moléculaire couplée au calcul des paramètres de la théorie de Marcus montre enfin que ce transfert électronique à longue distance est envisageable via une molécule d eau dont la position pontante stabilisée par le résidu Gln170 assure la connection entre les deux centres actifsPARIS-BIUSJ-Thèses (751052125) / SudocPARIS-BIUSJ-Physique recherche (751052113) / SudocSudocFranceF