Molecular dynamics simulation of apolipoprotein E3 lipid nanodiscs.

Nanodiscs are binary discoidal complexes of a phospholipid bilayer circumscribed by belt-like helical scaffold proteins. Using coarse-grained and all-atom molecular dynamics simulations, we explore the stability, size, and structure of nanodiscs formed between the N-terminal domain of apolipoprotein E3 (apoE3-NT) and variable number of 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) molecules. We study both parallel and antiparallel double-belt configurations, consisting of four proteins per nanodisc. Our simulations predict nanodiscs containing between 240 and 420 DMPC molecules to be stable. The antiparallel configurations exhibit an average of 1.6 times more amino acid interactions between protein chains and 2 times more ionic contacts, compared to the parallel configuration. With one exception, DMPC order parameters are consistently larger in the antiparallel configuration than in the parallel one. In most cases, the root mean square deviation of the positions of the protein backbone atoms is smaller in the antiparallel configuration. We further report nanodisc size, thickness, radius of gyration, and solvent accessible surface area. Combining all investigated parameters, we hypothesize the antiparallel protein configuration leading to more stable and more rigid nanodiscs than the parallel one.

Synthesis and Properties of Azahomocorannulenyl Cations and Radicals.

Cycloheptatrienyl (tropyl) molecules are representative non-alternant hydrocarbons that offer interesting chemistry because of their unique structures and properties. However, there have been a limited number of polycyclic aromatic tropyl cations and radicals reported in the literature. Herein, we report the synthesis of a series of azahomocorannulene derivatives, where the key reactions are a 1,3-dipolar cycloaddition of polycyclic aromatic azomethine ylides with dibenzotropone and a subsequent palladium-catalyzed cyclization. X-ray diffraction analysis revealed that the obtained azahomocorannulenyl cation and radical adopt planar structures and exhibit unique packing structures. Their electronic and optical properties were investigated experimentally and theoretically to reveal their aromatic character.

Molecular Dynamics Simulation of Apolipoprotein E3 Lipid Nanodiscs.

Nanodiscs are binary discoidal complexes of a phospholipid bilayer circumscribed by belt-like helical scaffold proteins. Using coarse-grained and all-atom molecular dynamics simulations, we explore the stability, size, and structure of nanodiscs formed between the N-terminal domain of apolipoprotein E3 (apoE3-NT) and variable number of 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) molecules. We study both parallel and antiparallel double-belt configurations, consisting of four proteins per nanodisc. Our simulations predict nanodiscs containing between 240 and 420 DMPC molecules to be stable. The antiparallel configurations exhibit an average of 1.6 times more amino acid interactions between protein chains and 2 times more ionic contacts, compared to the parallel configuration. With one exception, DMPC order parameters are consistently larger in the antiparallel configuration than in the parallel one. In most cases, the root mean square deviation of the positions of the protein backbone atoms is smaller in the antiparallel configuration. We further report nanodisc size, thickness, radius of gyration, and solvent accessible surface area. Combining all investigated parameters, we hypothesize the antiparallel protein configuration leading to more stable and more rigid nanodiscs than the parallel one.

TURBOMOLE: Today and Tomorrow.

TURBOMOLE is a highly optimized software suite for large-scale quantum-chemical and materials science simulations of molecules, clusters, extended systems, and periodic solids. TURBOMOLE uses Gaussian basis sets and has been designed with robust and fast quantum-chemical applications in mind, ranging from homogeneous and heterogeneous catalysis to inorganic and organic chemistry and various types of spectroscopy, light-matter interactions, and biochemistry. This Perspective briefly surveys TURBOMOLE's functionality and highlights recent developments that have taken place between 2020 and 2023, comprising new electronic structure methods for molecules and solids, previously unavailable molecular properties, embedding, and molecular dynamics approaches. Select features under development are reviewed to illustrate the continuous growth of the program suite, including nuclear electronic orbital methods, Hartree-Fock-based adiabatic connection models, simplified time-dependent density functional theory, relativistic effects and magnetic properties, and multiscale modeling of optical properties.

Ab Initio Simulation of the Ultrafast Circular Dichroism Spectrum of Provitamin D Ring-Opening.

We present a method to simulate ultrafast pump-probe time-resolved circular dichroism (TRCD) spectra based on time-dependent density functional theory trajectory surface hopping. The method is applied to simulate the TRCD spectrum along the photoinduced ring-opening of provitamin D. Simulations reveal that the initial decay of the signal is due to excited state relaxation, forming the rotationally flexible previtamin D. We further show that oscillations in the experimental TRCD spectrum arise from isomerizations between previtamin D rotamers with different chirality, which are associated with the helical conformation of the triene unit. We give a detailed description of the formation dynamics of different rotamers, playing a key role in the natural regulation of vitamin D photosynthesis. Going beyond the sole extraction of decay rates, simulations greatly increase the amount of information that can be retrieved from ultrafast TRCD, making it a sensitive tool to unravel details in the subpicosecond dynamics of photoinduced chirality changes.

Ab initio simulation of the ultrafast circular dichroism spectrum of provitamin D ring-opening.

We present a method to simulate ultrafast pump-probe time-resolved circular dichroism (TRCD) spectra based on time-dependent density functional theory trajectory surface hopping. The method is applied to simulate the TRCD spectrum along the photoinduced ring-opening of provitamin D. Simulations reveal that the initial decay of the signal is due to excited state relaxation, forming the rotationally flexible previtamin D. We further show that oscillations in the experimental TRCD spectrum arise from isomerizations between previtamin D rotamers with different chirality, which are associated with the helical conformation of the triene unit. We give a detailed description of the formation dynamics of different rotamers, playing a key role in the natural regulation vitamin D photosynthesis. Going beyond the sole extraction of decay rates, simulations greatly increase the amount of information that can be retrieved from ultrafast TRCD, making it a sensitive tool to unravel details in the sub-picosecond dynamics of photoinduced chirality changes.

Energetically unfavorable protein angles: Exploration of a conserved dihedral angle in triosephosphate isomerase.

Over the past 3.5 billion years of evolution, enzymes have adopted a myriad of conformations to suit life on earth. However, torsional angles of proteins have settled into limited zones of energetically favorable dihedrals observed in Ramachandran plots. Areas outside said zones are believed to be disallowed to all amino acids, except glycine, due to steric hindrance. Triosephosphate isomerase (TIM), a homodimer with a catalytic rate approaching the diffusion limit, contains an active site lysine residue (K13) with dihedrals within the fourth quadrant (Φ = +51/Ψ = -143). Both the amino acid and the dihedral angles are conserved across all species of TIM and known crystal structures regardless of ligand. Only crystal structures of the engineered monomeric version (1MSS) show accepted ß-sheet dihedral values of Φ = -135/Ψ = +170 but experiments show a 1000-fold loss in activity. Based on these results, we hypothesized that adopting the unfavorable torsion angle for K13 contributes to catalysis. Using both, computational and experimental approaches, four residues that interact with K13 (N11, M14, E97, and Q64) were mutated to alanine. In silico molecular dynamics (MD) simulations were performed using 2JK2 unliganded human TIM as a starting structure. Ramachandran plots, containing K13 dihedral values reveal full or partial loss of disallowed zone angles. N11A showed no detectable catalytic activity and lost the unfavorable K13 dihedral angles across four separate force fields during simulation while all other mutants plus wild type retained activity and retained the conserved K13 dihedral angles.

Applicability of the Thawed Gaussian Wavepacket Dynamics to the Calculation of Vibronic Spectra of Molecules with Double-Well Potential Energy Surfaces.

Simulating vibrationally resolved electronic spectra of anharmonic systems, especially those involving double-well potential energy surfaces, often requires expensive quantum dynamics methods. Here, we explore the applicability and limitations of the recently proposed single-Hessian thawed Gaussian approximation for the simulation of spectra of systems with double-well potentials, including 1,2,4,5-tetrafluorobenzene, ammonia, phosphine, and arsine. This semiclassical wavepacket approach is shown to be more robust and to provide more accurate spectra than the conventional harmonic approximation. Specifically, we identify two cases in which the Gaussian wavepacket method is especially useful due to the breakdown of the harmonic approximation: (i) when the nuclear wavepacket is initially at the top of the potential barrier but delocalized over both wells, e.g., along a low-frequency mode, and (ii) when the wavepacket has enough energy to classically go over the low potential energy barrier connecting the two wells. The method is efficient and requires only a single classical ab initio molecular dynamics trajectory, in addition to the data required to compute the harmonic spectra. We also present an improved algorithm for computing the wavepacket autocorrelation function, which guarantees that the evaluated correlation function is continuous for arbitrary size of the time step.

Probing the Formation and Conformational Relaxation of Previtamin D3 and Analogues in Solution and in Lipid Bilayers.

The photosynthesis of vitamin D3 in mammalian skin results from UV-B irradiation of provitamin D3 (7-dehydrocholesterol, DHC) at ca. 290 nm. Upon return to the ground state, the hexatriene product, previtamin D3, undergoes a conformational equilibration between helical gZg and more planar tZg and tZt forms. The helical gZg forms provide a pathway for the formation of vitamin D3 via a [1,7]-sigmatropic hydrogen shift. Steady state photolysis and UV transient absorption spectroscopy are combined to explore the conformational relaxation of previtamin D3 formed from DHC in isotropic solution and confined to lipid bilayers chosen to model the biological cell membrane. The results are compared with measurements for two analogues: previtamin D2 formed from ergosterol (provitamin D2) and previtamin D3 acetate formed from DHC acetate. The resulting spectral dynamics are interpreted in the context of simulations of optical excitation energy and oscillator strength as a function of conformation. In solution, the relaxation dynamics and steady state product distributions of the three compounds are nearly identical, favoring tZg forms. When confined to lipid bilayers, the heterogeneity and packing forces alter the conformational distributions and enhance the population of a gZg conformer capable of vitamin D formation.

Elucidating an Atmospheric Brown Carbon Species-Toward Supplanting Chemical Intuition with Exhaustive Enumeration and Machine Learning.

Brown carbon (BrC) is involved in atmospheric light absorption and climate forcing and can cause adverse health effects. Understanding the formation mechanisms and molecular structure of BrC is of key importance in developing strategies to control its environment and health impact. Structure determination of BrC is challenging, due to the lack of experiments providing molecular fingerprints and the sheer number of molecular candidates with identical mass. Suggestions based on chemical intuition are prone to errors due to the inherent bias. We present an unbiased algorithm, using graph-based molecule generation and machine learning, which can identify all molecular structures of compounds involved in biomass burning and the composition of BrC. We apply this algorithm to C12H12O7, a light-absorbing "test case" molecule identified in chamber experiments on the aqueous photo-oxidation of syringol, a prevalent marker in wood smoke. Of the 260 million molecular graphs, the algorithm leaves only 36,518 (0.01%) as viable candidates matching the spectrum. Although no unique molecular structure is obtained from only a chemical formula and a UV/vis absorption spectrum, we discuss further reduction strategies and their efficacy. With additional data, the method can potentially more rapidly identify isomers extracted from lab and field aerosol particles without introducing human bias.

First principles theoretical spectroscopy of methylene blue: Between limitations of time-dependent density functional theory approximations and its realistic description in the solvent.

Methylene blue [3,7-Bis(di-methylamino) phenothiazin-5-ium chloride] is a phenothiazine dye with applications as a sensitizer for photodynamic therapy, photoantimicrobials, and dye-sensitized solar cells. Time-dependent density functional theory (TDDFT), based on (semi)local and global hybrid exchange-correlation functionals, fails to correctly describe its spectral features due to known limitations for describing optical excitations of π-conjugated systems. Here, we use TDDFT with a non-empirical optimally tuned range-separated hybrid functional to explore the optical excitations of gas phase and solvated methylene blue. We compute solvated configurations using molecular dynamics and an iterative procedure to account for explicit solute polarization. We rationalize and validate that by extrapolating the optimized range separation parameter to an infinite amount of solvating molecules, the optical gap of methylene blue is well described. Moreover, this method allows us to resolve contributions from solvent-solute intermolecular interactions and dielectric screening. We validate our results by comparing them to first-principles calculations based on the GW+Bethe-Salpeter equation approach and experiment. Vibronic calculations using TDDFT and the generating function method account for the spectra's subbands and bring the computed transition energies to within 0.15 eV of the experimental data. This methodology is expected to perform equivalently well for describing solvated spectra of π-conjugated systems.

TURBOMOLE: Modular program suite for ab initio quantum-chemical and condensed-matter simulations.

TURBOMOLE is a collaborative, multi-national software development project aiming to provide highly efficient and stable computational tools for quantum chemical simulations of molecules, clusters, periodic systems, and solutions. The TURBOMOLE software suite is optimized for widely available, inexpensive, and resource-efficient hardware such as multi-core workstations and small computer clusters. TURBOMOLE specializes in electronic structure methods with outstanding accuracy-cost ratio, such as density functional theory including local hybrids and the random phase approximation (RPA), GW-Bethe-Salpeter methods, second-order Møller-Plesset theory, and explicitly correlated coupled-cluster methods. TURBOMOLE is based on Gaussian basis sets and has been pivotal for the development of many fast and low-scaling algorithms in the past three decades, such as integral-direct methods, fast multipole methods, the resolution-of-the-identity approximation, imaginary frequency integration, Laplace transform, and pair natural orbital methods. This review focuses on recent additions to TURBOMOLE's functionality, including excited-state methods, RPA and Green's function methods, relativistic approaches, high-order molecular properties, solvation effects, and periodic systems. A variety of illustrative applications along with accuracy and timing data are discussed. Moreover, available interfaces to users as well as other software are summarized. TURBOMOLE's current licensing, distribution, and support model are discussed, and an overview of TURBOMOLE's development workflow is provided. Challenges such as communication and outreach, software infrastructure, and funding are highlighted.

Azologization and repurposing of a hetero-stilbene-based kinase inhibitor: towards the design of photoswitchable sirtuin inhibitors.

The use of light as an external trigger to change ligand shape and as a result its bioactivity, allows the probing of pharmacologically relevant systems with spatiotemporal resolution. A hetero-stilbene lead resulting from the screening of a compound that was originally designed as kinase inhibitor served as a starting point for the design of photoswitchable sirtuin inhibitors. Because the original stilbenoid structure exerted unfavourable photochemical characteristics it was remodelled to its heteroarylic diazeno analogue. By this intramolecular azologization, the shape of the molecule was left unaltered, whereas the photoswitching ability was improved. As anticipated, the highly analogous compound showed similar activity in its thermodynamically stable stretched-out (E)-form. Irradiation of this isomer triggers isomerisation to the long-lived (Z)-configuration with a bent geometry causing a considerably shorter end-to-end distance. The resulting affinity shifts are intended to enable real-time photomodulation of sirtuins in vitro.

Calculation of vibrationally resolved absorption spectra of acenes and pyrene.

The absorption spectra of naphthalene, anthracene, pentacene and pyrene in the ultraviolet-visible (UV-Vis) range have been simulated by using an efficient real-time generating function method that combines calculated adiabatic electronic excitation energies with vibrational energies of the excited states. The vertical electronic excitation energies have been calculated at the density functional theory level using the PBE0 functional and at the second-order approximate coupled-cluster level (CC2). The absorption spectra have been calculated at the PBE0 level for the studied molecules and at the CC2 level for naphthalene. The transition probabilities between vibrationally resolved states were calculated by using the real-time generating function method employing the full Duschinsky formalism. The absorption spectrum for naphthalene calculated at the PBE0 and CC2 levels agrees well with the experimental one after the simulated spectra have been blue-shifted by 0.48 eV and 0.12 eV at the PBE0 and CC2 level, respectively. The absorption spectra for anthracene, pentacene and pyrene simulated at the PBE0 level agree well with the experimental ones when they are shifted by 0.49 eV, 0.57 eV and 0.46 eV, respectively. The strongest transitions of the main vibrational bands have been assigned.

Generating Function Approach to Single Vibronic Level Fluorescence Spectra.

An efficient time-dependent generating function method to compute vibronic emission and absorption spectra arising from transitions from a singly excited vibrational initial state is presented. In contrast to existing finite temperature approaches that intrinsically contain these transitions weighted by a Boltzmann factor, the current approach allows one to calculate these transitions individually. Using vibrational frequencies and normal modes computed by the second-order approximate coupled cluster (CC2) method, this formalism is used to compute the single vibronic level (SVL) fluorescence spectra of anthracene. Calculated spectra are in excellent agreement with spectra measured in jet-cooled expansion experiments. Duschinsky mixing is necessary to explain intensities of certain peaks. In a few cases, CC2, however, underestimates Duschinsky mixing, leading to too low peak intensities. An empirical correction of the Duschinsky matrix is presented. The presented method has the potential to facilitate the assignment and interpretation of SVL fluorescence spectra.

Tuning the photoreactivity of Z-hexatriene photoswitches by substituents - a non-adiabatic molecular dynamics study.

To understand how substituents can be used to increase the quantum yield of photochemical electrocyclic ring-closing of the Z-hexa-1,3,5-triene (HT) photoswitch forming cyclohexadiene (CHD), we investigate the S1 photo dynamics of HT and its derivatives 2,5-dimethyl-HT (DMHT), 2-isopropyl-5-methyl-HT (2,5-IMHT), 1-isopropyl-4-methyl-HT (1,4-IMHT), and 2,5-diisopropyl-HT (DIHT) using time-dependent density functional theory surface hopping dynamics. We report detailed photoproduct distributions, formation mechanisms, branching ratios, and wavelength-dependent product quantum yields. Most products have been confirmed experimentally and include all-trans HT derivatives, cyclopropanes, cyclobutenes, cyclopentene, cyclohexadienes, and bicyclic compounds. Regarding CHD formation, we find that for the 2,5-substituted derivatives DMHT, 2,5-IMHT, and DIHT, the branching ratios increase with increasing size of the substituents. In contrast the branching ratios of the E/Z-isomerization decrease with increasing size of the substituents. Due to steric interactions, increasing the size of the substituents increases the amount of gZg rotamers in the ground state, which are prone to CHD formation and have lower E/Z-isomerization probability. Furthermore, we find [1,4], [1,5], and [1,6]-sigmatropic hydrogen shift reactions occurring at large percentages (5% to 15%); for sterical reasons these reactions stem from tZg conformers. DIHT shows the lowest percentage of side product formation among the 2,5-substituted molecules and highest CHD branching ratio; its CHD quantum yield can be increased up to more than 64%, by excitation of DIHT on the red tail of its absorption spectrum, whereas the Z/E-isomerization is reduced below 5% and side reactions practically vanish. This makes DIHT the best candidate for applications in molecular switches.

First-Principles Prediction of Wavelength-Dependent Product Quantum Yields.

We present a method to predict wavelength-dependent product quantum yields (PQYs) for photochemical reactions and applied it to Z/E-isomerization and several ring-closing reactions of Z-2,5-dimethyl-1,3,5-hexatriene and truncated previtamin D. Using branching ratios from surface hopping molecular dynamics, individual trajectories are correlated with the absorption spectra of their initial structures. The wavelength-dependent PQYs are computed by dividing the average spectrum of the initial structures of the product-forming trajectories by the average spectrum of all initial structures. Accurate absorption spectra are calculated using the correlated ADC(2) method with an implicit solvent. Calculations reproduce the experimentally found trend of increasing six-ring formation and decreasing Z/E-isomerization on the red side of the spectrum. Over all seven reactions studied, the mean absolute error (MAE) between experimental and calculated PQYs (MAE) amounts to 8.1%, and the largest MAE is 18.6%. For four reactions, predicted values agree quantitatively with experiments within 5.6%.

Nitrogen-Containing, Light-Absorbing Oligomers Produced in Aerosol Particles Exposed to Methylglyoxal, Photolysis, and Cloud Cycling.

Aqueous methylglyoxal chemistry has often been implicated as an important source of oligomers in atmospheric aerosol. Here we report on chemical analysis of brown carbon aerosol particles collected from cloud cycling/photolysis chamber experiments, where gaseous methylglyoxal and methylamine interacted with glycine, ammonium, or methylammonium sulfate seed particles. Eighteen N-containing oligomers were identified in the particulate phase by liquid chromatography/diode array detection/electrospray ionization high-resolution quadrupole time-of-flight mass spectrometry. Chemical formulas were determined and, for 6 major oligomer products, MS2 fragmentation spectra were used to propose tentative structures and mechanisms. Electronic absorption spectra were calculated for six tentative product structures by an ab initio second order algebraic-diagrammatic-construction/density functional theory approach. For five structures, matching calculated and measured absorption spectra suggest that they are dominant light-absorbing species at their chromatographic retention times. Detected oligomers incorporated methylglyoxal and amines, as expected, but also pyruvic acid, hydroxyacetone, and significant quantities of acetaldehyde. The finding that ∼80% (by mass) of detected oligomers contained acetaldehyde, a methylglyoxal photolysis product, suggests that daytime methylglyoxal oligomer formation is dominated by radical addition mechanisms involving CH3CO*. These mechanisms are evidently responsible for enhanced browning observed during photolytic cloud events.

The role of tachysterol in vitamin D photosynthesis - a non-adiabatic molecular dynamics study.

To investigate the role of tachysterol in the photophysical/photochemical regulation of vitamin D photosynthesis, we studied its electronic absorption properties and excited state dynamics using time-dependent density functional theory (TDDFT), second-order approximate coupled cluster theory (CC2), and non-adiabatic surface hopping molecular dynamics in the gas phase. In excellent agreement with experiments, the simulated electronic spectrum shows a broad absorption band with a remarkably higher extinction coefficient than the other vitamin D photoisomers provitamin D, lumisterol, and previtamin D. The broad band arises from the spectral overlap of four different ground state rotamers. After photoexcitation, the first excited singlet state (S1) decays with a lifetime of 882 fs. The S1 dynamics is characterized by a strong twisting of the central double bond. In 96% of all trajectories this is followed by unreactive relaxation to the ground state near a conical intersection. The double-bond twisting in the chemically unreactive trajectories induces a strong interconversion between the different rotamers. In 2.3% of the trajectories we observed [1,5]-sigmatropic hydrogen shift forming the partly deconjugated toxisterol D1. 1.4% previtamin D formation is observed via hula-twist double bond isomerization. In both reaction channels, we find a strong dependence between photoreactivity and dihedral angle conformation: hydrogen shift only occurs in cEc and cEt rotamers and double bond isomerization occurs mainly in cEc rotamers. Hence, our study confirms the previously formed hypothesis that cEc rotamers are more prone to previtamin D formation than other isomers. In addition, we also observe the formation of a cyclobutene-toxisterol in the hot ground state in 3 trajectories (0.7%). Due to its large extinction coefficient and mostly unreactive behavior, tachysterol acts mainly as a Sun shield suppressing previtamin D formation. Tachysterol shows stronger toxisterol formation than previtamin D and can thus be seen as the major degradation route of vitamin D. Absorption of low energy ultraviolet light by the cEc rotamer can lead to previtamin D formation. In addition, the cyclobutene-toxisterol, which possibly reacts thermally to previtamin D, is also preferably formed at long wavelengths. These two mechanisms are consistent with the wavelength dependent photochemistry found in experiments. Our study reinforces a recent hypothesis that tachysterol constitutes a source of previtamin D when only low energy ultraviolet light is available, as it is the case in winter or in the morning and evening hours of the day.

That Little Extra Kick: Nonadiabatic Effects in Acetaldehyde Photodissociation.

The effect of nonadiabatic transitions on branching ratios, kinetic and internal energy distribution of fragments, and reaction mechanisms observed in acetaldehyde photodissociation is investigated by nonadiabatic molecular dynamics (NAMD) simulations using time-dependent hybrid density functional theory and Tully surface hopping. Homolytic bond breaking is approximately captured by allowing spin symmetry to break. The NAMD simulations reveal that nonadiabatic transitions selectively enhance the kinetic energy of certain internal degrees of freedom within approximately 50 fs. Branching ratios from NAMD and conventional "hot" Born-Oppenheimer molecular dynamics (BOMD) are similar and qualitatively agree with experiment. However, as opposed to the BOMD simulations, NAMD captures the high-energy tail of the experimental kinetic energy distribution. The extra "kick" of the nuclei in the direction of the nonadiabatic coupling vector results from nonadiabatic transitions close to conical intersections. From a mechanistic perspective, the nonadiabatic effects favor asynchronous over synchronous fragmentation and tend to suppress roaming.