Elucidating Heavy Atom Tunneling Kinetics in the Cope Rearrangement of Semibullvalene.

In this work, we characterize the temperature dependence of kinetic properties in heavy atom tunneling reactions by means of molecular dynamics simulations, including nuclear quantum effects (NQEs) via Path Integral theory. To this end, we consider the prototypical Cope rearrangement of semibullvalene. The reaction was studied in the 25-300K temperature range observing that the inclusion of NQEs modifies the temperature behavior of both free energy barriers and dynamical recrossing factors with respect to classical dynamics. Notably, while in classical simulations the activation free energy shows a very weak temperature dependence, it becomes strongly dependent on temperature when NQEs are included. This temperature behavior shows a transition from a regime where the quantum effects are limited and can mainly be traced back to zero point energy, to a low temperature regime where tunneling plays a dominant role. In this regime, the free energy curve tunnels below the potential energy barrier along the reaction coordinate,  allowing much faster reaction rates. Finally, the temperature dependence of the rate constants obtained from molecular dynamics simulations was compared with available experimental data and with semi-classical transition state theory calculations, showing comparable behaviors and similar transition temperatures from  thermal to (deep) tunneling regime.

Light-induced infrared difference spectroscopy on three different forms of orange carotenoid protein: focus on carotenoid vibrations.

Orange carotenoid protein (OCP) is a photoactive carotenoprotein involved in photoprotection of cyanobacteria, which uses a keto-catorenoid as a chromophore. When it absorbs blue-green light, it converts from an inactive OCPO orange form to an activated OCPR red form, the latter being able to bind the light-harvesting complexes facilitating thermal dissipation of the excess of absorbed light energy. Several research groups have focused their attention on the photoactivation mechanism, characterized by several steps, involving both carotenoid photophysics and protein conformational changes. Among the used techniques, time-resolved IR spectroscopy have the advantage of providing simultaneously information on both the chromophore and the protein, giving thereby the possibility to explore links between carotenoid dynamics and protein dynamics, leading to a better understanding of the mechanism. However, an appropriate interpretation of data requires previous assignment of marker IR bands, for both the carotenoid and the protein. To date, some assignments have concerned specific α-helices of the OCP backbone, but no specific marker band for the carotenoid was identified on solid ground. This paper provides evidence for the assignment of putative marker bands for three carotenoids bound in three different OCPs: 3'-hydroxyechineone (3'-hECN), echinenone (ECN), canthaxanthin (CAN). Light-induced FTIR difference spectra were recorded in H2O and D2O and compared with spectra of isolated carotenoids. The use of DFT calculations allowed to propose a description for the vibrations responsible of several IR bands. Interestingly, most bands are located at the same wavenumber for the three kinds of OCPs suggesting that the conformation of the three carotenoids is the same in the red and in the orange form. These results are discussed in the framework of recent time-resolved IR studies on OCP.

Quasi-classical simulations of resonance Raman spectra based on path integral linearization.

Based on a linearization approximation coupled with path integral formalism, we propose a method derived from the propagation of quasi-classical trajectories to simulate resonance Raman spectra. This method is based on ground state sampling followed by an ensemble of trajectories on the mean surface between the ground and excited states. The method was tested on three models and compared to a quantum mechanics solution based on a sum-over-states approach: harmonic and anharmonic oscillators and the HOCl molecule (hypochlorous acid). The method proposed is able to correctly characterize resonance Raman scattering and enhancement, including the description of overtones and combination bands. The absorption spectrum is obtained at the same time, and the vibrational fine structure can be reproduced for long excited state relaxation times. The method can also be applied to dissociating excited states (as is the case for HOCl).

Efficient and Accurate Description of Diels-Alder Reactions Using Density Functional Theory.

Modeling chemical reactions using Quantum Chemistry is a widely used predictive strategy capable to complement experiments in order to understand the intrinsic mechanisms guiding the chemicals towards the most favorable reaction products. However, at this purpose, it is mandatory to use reliable and computationally tractable theoretical methods. In this work, we focus on six Diels-Alder reactions of increasing complexity and perform an extensive benchmark of middle- to low-cost computational approaches to predict the characteristic reactions energy barriers. We found that Density Functional Theory, using the ωB97XD, LC-ωPBE, CAM-B3LYP, M11 and MN12SX functionals, with empirical dispersion corrections coupled to an affordable 6-31G basis set, provides quality results for this class of reactions, at a small computational effort. Such efficient and reliable simulation protocol opens perspectives for hybrid QM/MM molecular dynamics simulations of Diels-Alder reactions including explicit solvation.

Quantum versus classical unimolecular fragmentation rate constants and activation energies at finite temperature from direct dynamics simulations.

In the present work, we investigate how nuclear quantum effects modify the temperature dependent rate constants and, consequently, the activation energies in unimolecular reactions. In the reactions under study, nuclear quantum effects mainly stem from the presence of a large zero point energy. Thus, we investigate the behavior of methods compatible with direct dynamics simulations, the quantum thermal bath (QTB) and ring polymer molecular dynamics (RPMD). To this end, we first compare them with quantum reaction theory for a model Morse potential before extending this comparison to molecular models. Our results show that, in particular in the temperature range comparable with or lower than the zero point energy of the system, the RPMD method is able to correctly capture nuclear quantum effects on rate constants and activation energies. On the other hand, although the QTB provides a good description of equilibrium properties including zero-point energy effects, it largely overestimates the rate constants. The origin of the different behaviours is in the different distance distributions provided by the two methods and in particular how they differently describe the tails of such distributions. The comparison with transition state theory shows that RPMD can be used to study fragmentation of complex systems for which it may be difficult to determine the multiple reaction pathways and associated transition states.

Implementing Historical Controls in Oncology Trials.

Drug development in oncology has broadened from mainly considering randomized clinical trials to also including single-arm trials tailored for very specific subtypes of cancer. They often use historical controls, and this article discusses benefits and risks of this paradigm and provide various regulatory and statistical considerations. While leveraging the information brought by historical controls could potentially shorten development time and reduce the number of patients enrolled, a careful selection of the past studies, a prespecified statistical analysis accounting for the heterogeneity between studies, and early engagement with regulators will be key to success. Although both the European Medicines Agency and the U.S. Food and Drug Administration have already approved medicines based on nonrandomized experiments, the evidentiary package can be perceived as less comprehensive than randomized experiments. Use of historical controls, therefore, is better suited for cases of high unmet clinical need, where the disease course is well characterized and the primary endpoint is objective. IMPLICATIONS FOR PRACTICE: Incorporating historical data in single-arm oncology trials has the potential to accelerate drug development and to reduce the number of patients enrolled, compared with standard randomized controlled clinical trials. Given the lack of blinding and randomization, such an approach is better suited for cases of high unmet clinical need and/or difficult experimental situations, in which the trajectory of the disease is well characterized and the endpoint can be measured objectively. Careful pre-specification and selection of the historical data, matching of the patient characteristics with the concurrent trial data, and innovative statistical methodologies accounting for between-study variation will be needed. Early engagement with regulators (e.g., via Scientific Advice) is highly recommended.

Determination of kinetic properties in unimolecular dissociation of complex systems from graph theory based analysis of an ensemble of reactive trajectories.

In this paper, we report how graph theory can be used to analyze an ensemble of independent molecular trajectories, which can react during the simulation time-length, and obtain structural and kinetic information. This method is totally general and here is applied to the prototypical case of gas phase fragmentation of protonated cyclo-di-glycine. This methodology allows us to analyze the whole set of trajectories in an automatic computer-based way without the need of visual inspection but by getting all the needed information. In particular, we not only determine the appearance of different products and intermediates but also characterize the corresponding kinetics. The use of colored graph and canonical labeling allows for the correct characterization of the chemical species involved. In the present case, the simulations consist of an ensemble of unimolecular fragmentation trajectories at constant energy such that from the rate constants at different energies, the threshold energy can also be obtained for both global and specific pathways. This approach allows for the characterization of ion-molecule complexes, likely through a roaming mechanism, by properly taking into account the elusive nature of such species. Finally, it is possible to directly obtain the theoretical mass spectrum of the fragmenting species if the reacting system is an ion as in the specific example.

Infrared-Assisted Synthesis of Prebiotic Glycine.

A novel approach has been developed to synthesize complex organic molecules (COMs) relevant to prebiotic chemistry, using infrared (IR) radiation to trigger the reaction. An original laboratory reactor working at low gas density and using IR irradiation was developed. In this way, glycine, the simplest brick of life, has been synthesized by assisting ion-molecule reaction with IR laser light. The ion-molecule complex constituted by acetic acid and hydroxylamine was formed in a mass spectrometer reactor and then irradiated with IR photons. As photoproducts, we obtained both glycine structures and some of its isomers. Anharmonic vibrational frequency calculations and fragmentation dynamics simulations allow for a better interpretation of the experimental data. This novel approach can be now extended to study other new synthetic pathways responsible for the formation of further COMs also with potential prebiotic relevance.

Collisional dynamics simulations revealing fragmentation properties of Zn(ii)-bound poly-peptide.

Chemical dynamics simulations are performed to study the collision induced gas phase unimolecular fragmentation of a model peptide with the sequence acetyl-His1-Cys2-Gly3-Pro4-Tyr5-His6-Cys7 (analogue methanobactin peptide-5, amb5) and in particular to explore the role of zinc binding in reactivity. Fragmentation pathways, their mechanisms, and collision energy transfer are discussed. The probability distributions of the pathways are compared with the results of the experimental IM-MS, MS/MS spectrum and previous thermal simulations. Collisional activation gives both statistical and non-statistical fragmentation pathways with non-statistical shattering mechanisms accounting for a relevant percentage of reactive trajectories, becoming dominant at higher energies. The tetra-coordination of zinc changes qualitative and quantitative fragmentation, in particular the shattering. The collision energy threshold for the shattering mechanism was found to be 118.9 kcal mol-1 which is substantially higher than the statistical Arrhenius activation barrier of 35.8 kcal mol-1 identified previously during thermal simulations. This difference can be attributed to the tetra-coordinated zinc complex that hinders the availability of the sidechains to undergo direct collision with the Ar projectile.

Exploring reactivity and product formation in N(4S) collisions with pristine and defected graphene with direct dynamics simulations.

Atomic nitrogen is formed in the high-temperature shock layer of hypersonic vehicles and contributes to the ablation of their thermal protection systems (TPSs). To gain atomic-level understanding of the ablation of carbon-based TPS, collisions of hyperthermal atomic nitrogen on representative carbon surfaces have recently be investigated using molecular beams. In this work, we report direct dynamics simulations of atomic-nitrogen [N(4S)] collisions with pristine, defected, and oxidized graphene. Apart from non-reactive scattering of nitrogen atoms, various forms of nitridation of graphene were observed in our simulations. Furthermore, a number of gaseous molecules, including the experimentally observed CN molecule, have been found to desorb as a result of N-atom bombardment. These results provide a foundation for understanding the molecular beam experiment and for modeling the ablation of carbon-based TPSs and for future improvement of their properties.

On the Use of Quantum Thermal Bath in Unimolecular Fragmentation Simulation.

In the present work, we have investigated the possibility of using the quantum thermal bath (QTB) method in molecular simulations of unimolecular dissociation processes. Notably, QTB is used in introducing nuclear quantum effects with a computational time, which is basically the same as in Newtonian simulations. At this end, we have considered the model fragmentation of CH4 for which an analytical function is present in the literature. Moreover, based on the same model, a microcanonical algorithm, which monitors the zero-point energy of products and eventually modifies trajectories, was recently proposed. We have thus compared classical and quantum rate constants with these different models. QTB seems to correctly reproduce some quantum features, in particular the difference between classical and quantum activation energies, making it a promising method to study, with molecular simulations, unimolecular fragmentation of much complex systems. The role of a QTB thermostat in rotational degrees of freedom is also analyzed and discussed.

l-Cysteine Modified by S-Sulfation: Consequence on Fragmentation Processes Elucidated by Tandem Mass Spectrometry and Chemical Dynamics Simulations.

Low-energy collision-induced dissociation (CID) of deprotonated l-cysteine S-sulfate, [cysS-SO3]-, delivered in the gas phase by electrospray ionization, has been found to provide a means to form deprotonated l-cysteine sulfenic acid, which is a fleeting intermediate in biological media. The reaction mechanism underlying this process is the focus of the present contribution. At the same time, other novel species are formed, which were not observed in previous experiments. To understand fragmentation pathways of [cysS-SO3]-, reactive chemical dynamics simulations coupled with a novel algorithm for automatic determination of intermediates and transition states were performed. This approach has allowed the identification of the mechanisms involved and explained the experimental fragmentation pathways. Chemical dynamics simulations have shown that a roaming-like mechanism can be at the origin of l-cysteine sulfenic acid.

Threshold for shattering fragmentation in collision-induced dissociation of the doubly protonated tripeptide TIK(H+)2.

In a recent direct dynamics simulations of the collision induced dissociation (CID) of the doubly protonated tripeptide threonine-isoleucine-lysine and threonine-leucine-lysine ions, TIK(H+)2 and TLK(H+)2, a shattering fragmentation mechanism was found, in which the ion fragmented upon impact with N2 (Z. Homayoon et al., Phys. Chem. Chem. Phys., 2018, 20, 3614). In using models to interpret experiments of biological ion CID, it is important to know the collision energy threshold for the shattering mechanism. In the work presented here, direct dynamics simulations were performed to study shattering fragmentation versus the collision energy (Erel) for N2 + TIK(H+)2. From the probability of shattering fragmentation and the minimum energy transfer for fragmentation versus Erel, a threshold of ∼55 kcal mol-1 was identified for N2 + TIK(H+)2 shattering fragmentation. This threshold is substantially higher than the lowest activation energy of 14.7 kcal mol-1, found from direct dynamics simulations, for the thermal dissociation of TIK(H+)2.

Chemical dynamics simulations of CID of peptide ions: comparisons between TIK(H+)2 and TLK(H+)2 fragmentation dynamics, and with thermal simulations.

Gas phase unimolecular fragmentation of the two model doubly protonated tripeptides threonine-isoleucine-lysine (TIK) and threonine-leucine-lysine (TLK) is studied using chemical dynamics simulations. Attention is focused on different aspects of collision induced dissociation (CID): fragmentation pathways, energy transfer, theoretical mass spectra, fragmentation mechanisms, and the possibility of distinguishing isoleucine (I) and leucine (L). Furthermore, discussion is given regarding the differences between single collision CID activation, which results from a localized impact between the ions and a colliding molecule N2, and previous thermal activation simulation results; Z. Homayoon, S. Pratihar, E. Dratz, R. Snider, R. Spezia, G. L. Barnes, V. Macaluso, A. Martin-Somer and W. L. Hase, J. Phys. Chem. A, 2016, 120, 8211-8227. Upon thermal activation unimolecular fragmentation is statistical and in accord with RRKM unimolecular rate theory. Simulations show that in collisional activation some non-statistical fragmentation occurs, including shattering, which is not present when the ions dissociate statistically. Products formed by non-statistical shattering mechanisms may be related to characteristic mass spectrometry peaks which distinguish the two isomers I and L.

Gas Phase Synthesis of Protonated Glycine by Chemical Dynamics Simulations.

In the present work, we investigated the reaction dynamics that will possibly lead to the formation of protonated glycine by an ion-molecule collision. In particular, two analogous reactions were studied: NH3OH+ + CH3COOH and NH2OH2+ + CH3COOH that were suggested by previous experiments to be able to form protonated glycine loosing a neutral water molecule. Chemical dynamics simulations show that both reactants can form a molecule with the mass of the protonated glycine but with different structures, if some translational energy is given to the system. The reaction mechanisms for the most relevant product isomers are discussed as well as the role of collision energy in determining reaction products. Finally, in comparing collision dynamics at room and at very low initial internal temperature of the reactants, the same behavior was obtained for forming the protonated glycine isomers products. This supports the use of standard gas phase ion-chemistry setups to study collision-induced reactivity as a model for astrophysical cold conditions, when some relative translation energy is given to the system.

Unimolecular Fragmentation of Deprotonated Diproline [Pro2-H]- Studied by Chemical Dynamics Simulations and IRMPD Spectroscopy.

Dissociation chemistry of the diproline anion [Pro2-H]- is studied using chemical dynamics simulations coupled with quantum-chemical calculations and RRKM analysis. Pro2- is chosen due to its reduced size and the small number of sites where deprotonation can take place. The mechanisms leading to the two dominant collision-induced dissociation (CID) product ions are elucidated. Trajectories from a variety of isomers of [Pro2-H]- were followed in order to sample a larger range of possible reactivity. While different mechanisms yielding y1- product ions are proposed, there is only one mechanism yielding the b2- ion. This mechanism leads to formation of a b2- fragment with a diketopiperazine structure. The sole formation of a diketopiperazine b2 sequence ion is experimentally confirmed by infrared ion spectroscopy of the fragment anion. Furthermore, collisional and internal energy activation simulations are used in parallel to identify the different dynamical aspects of the observed reactivity.

How Does CeIII Nitrate Dissolve in a Protic Ionic Liquid? A Combined Molecular Dynamics and EXAFS Study.

A diluted solution of Ce(NO3 )3 in the protic ionic liquid (IL) ethylammonium nitrate (EAN) was investigated using molecular dynamics (MD) simulations and extended X-ray absorption fine structure (EXAFS) spectroscopy. For the first time polarizable effects were included in the MD force field to describe a heavy metal ion in a protic IL, but, unlike water, they were found to be unessential. The CeIII ion first solvation shell is formed by nitrate ions arranged in an icosahedral structure, and an equilibrium between monodentate and bidentate ligands is present in the solution. By combining distance and angular distribution functions it was possible to unambiguously identify this peculiar coordination geometry around the ions dissolved in solution. The metal ions are solvated within the polar domains of the EAN nanostructure and the dissolved salt induces almost no reorganization of the pre-existing structure of EAN upon solubilization.

Characterization of Protonated Model Disaccharides from Tandem Mass Spectrometry and Chemical Dynamics Simulations.

The fragmentation mechanisms of prototypical disaccharides have been studied herein by coupling tandem mass spectrometry (MS) with collisional chemical dynamics simulations. These calculations were performed by explicitly considering the collisions between the protonated sugar and the neutral target gas, which led to an ensemble of trajectories for each system, from which it was possible to obtain reaction products and mechanisms without pre-imposing them. The ß-aminoethyl and aminopropyl derivatives of cellobiose, maltose, and gentiobiose were studied to observe differences in both the stereochemistry and the location of the glycosidic linkage. Chemical dynamics simulations of MS/MS and MS/MS/MS were used to suggest some primary and secondary fragmentation mechanisms for some experimentally observed product ions. These simulations provided some new insights into the fundamentals of the unimolecular dissociation of protonated sugars under collisional induced dissociation conditions.

Solvation Properties of the Actinide Ion Th(IV) in DMSO and DMSO:Water Mixtures through Polarizable Molecular Dynamics.

We have studied the solvation of Th4+ in water, in dimethyl sulfoxide (DMSO), and in their equimolar mixture by using molecular dynamics based on an Amoeba-derived polarizable force field. We have performed an extended structural analysis in order to provide a complete picture of the chemical-physical features of the interaction of Th4+ with the two solvents in their pure and mixed states. Through our simulations we found that, very likely, the first solvation shell in DMSO is not unlike the one found in pure water and contains 9 solvent molecules. The residence time of first shell of DMSO molecules is however much longer than the residence time of water. For the 1:1 mixture we present computational evidence that both water and DMSO participate in the solvation of Th4+ with a slight preference for the latter.

Excited state characterization of carbonyl containing carotenoids: a comparison between single and multireference descriptions.

Carotenoids can play multiple roles in biological photoreceptors thanks to their rich photophysics. In the present work, we have investigated six of the most common carbonyl containing carotenoids: echinenone, canthaxanthin, astaxanthin, fucoxanthin, capsanthin and capsorubin. Their excitation properties are investigated by means of a hybrid density functional theory (DFT) and multireference configuration interaction (MRCI) approach to elucidate the role of the carbonyl group: the bright transition is of ππ* character, as expected, but the presence of a C[double bond, length as m-dash]O moiety reduces the energy of nπ* transitions which may become closer to the ππ* transition, in particular as the conjugation chain decreases. This can be related to the presence of a low-lying charge transfer state typical of short carbonyl-containing carotenoids. The DFT/MRCI results are finally used to benchmark single-reference time-dependent DFT-based methods: among the investigated functionals, the meta-GGA (and in particular M11L and MN12L) functionals show to perform the best for all six investigated systems.