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Herein, we report a computational algorithm that follows a spectroscopist-driven elucidation process of the structure of an organic molecule based on IR, $^1$H and $^{13}$C NMR, and MS tabular data. The algorithm is independent from database searching and is based on a bottom-up approach, building the molecular structure from small structural fragments visible in spectra. It employs an analytical combinatorial approach with a graph search technique to determine the connectivity of structural fragments that is based on the analysis of the NMR spectra, to connect the identified structural fragments into a molecular structure. After the process is completed, the interface lists the compound candidates, which are visualized by the WolframAlpha computational knowledge engine within the interface. The candidates are ranked according to the predefined rules for analyzing the spectral data. The developed elucidator has a user-friendly web interface and is publicly available (http://schmarnica. si).

New technologies, prospects and scope, which are expected to have major applications in disease diagnostics and therapeutics, are introduced in the most emerging branch of pharmaceutical sciences known as Pharmaceutical nanotechnology. Pharmaceutical nanotechnology comprised of nano-sized products and which can be transformed in numerous ways to improve their characteristics. A Nanosponge is a novel and emerging technology, which offers targeted and controlled drug delivery for topical as well as oral use. The tiny sponges will circulate around the body. They touch and adhere to the surface of the particular target site and begin to release the drug in a regulated and predictable way. Since, the medication can be released at the specific target site rather than circulating around the body. It would be more effective for a specific dose given. The aqueous solubility of these sponges is another significant characteristic. This enables the efficient use of these systems for drugs with poor solubility. Both lipophilic as well as hydrophilic drugs can be loaded into nanosponges. Nanosponges drug delivery system has emerged as one of the most promising areas of life sciences.

Measuring rheological properties of cells in monolayers enables quantifying average cell properties in single experimental runs despite large cell-to-cell variations. Here, we describe how to modify a commercial rotational rheometer to accomplish the necessary precision for a monolayer rheometer and we delineate the steps for setting up experiments detecting average viscoelastic cell properties.

Carbohydrate chains are ubiquitous in the complex molecular processes of life. These highly diverse chains are recognized by a variety of protein receptors, enabling glycans to regulate many biological functions. High-resolution structures of protein-glycoligand complexes reveal the atomic details necessary to understand this level of molecular recognition and inform application-focused scientific and engineering pursuits. When experimental challenges hinder high-throughput determination of quality structures, computational tools can, in principle, fill the gap. In this work, we introduce GlycanDock, a residue-centric protein-glycoligand docking refinement algorithm developed within the Rosetta macromolecular modeling and design software suite. We performed a benchmark docking assessment using a set of 109 experimentally determined protein-glycoligand complexes as well as 62 unbound protein structures. The GlycanDock algorithm can sample and discriminate among protein-glycoligand models of native-like structural accuracy with statistical reliability from starting structures of up to 7 A root-mean-square deviation in the glycoligand ring atoms. We show that GlycanDock-refined models qualitatively replicated the known binding specificity of a bacterial carbohydrate-binding module. Finally, we present a protein-glycoligand docking pipeline for generating putative protein-glycoligand complexes when only the glycoligand sequence and unbound protein structure are known. In combination with other carbohydrate modeling tools, the GlycanDock docking refinement algorithm will accelerate research in the glycosciences.

Although surfactants have been widely used in skin care and other related applications, our knowledge about how surfactants interact with stratum corneum (SC) lipids remains limited. This work reports how surfactants interact with a lipid SC model by neutron diffraction and molecular dynamics (MD) simulations, focusing on examining the impact of surfactant molecular architecture. The surfactant-SC mixed membrane was constructed by an equimolar mixture of ceramide/cholesterol/fatty acids and surfactant at 1% molar ratio of total lipids. The arrangements of water and surfactant molecules in the membrane were obtained through neutron scattering length density (NSLD) profiles via contrast variation method, meanwhile, MD simulation clearly demonstrated the mechanism of hydration change in the surfactant-model SC mixed membrane. No drastic difference was detected in the repeating distance of the short periodicity phase (SPP) upon adding surfactants, however, it significantly enhanced the membrane hydration and reduced the amount of phase separated crystalline cholesterol, showing a strong dependence on surfactant chain length, branching and double bond. This work clearly demonstrates how surfactant architecture affects its interaction with the SC membrane, providing useful guidance for either choosing an existing surfactant or designing a new one for surfactant-based transdermal application.

As the past century has been characterized by waves of viral pandemics, there is an ever-growing role for molecular simulation-based research. In this study, we utilize all-atom molecular dynamics to simulate an enterovirus-D68 capsid and examine the dependency of viral capsid dynamics and properties on AMBER and CHARMM force fields. Out of the six force fields studied, we note that CHARMM36m and CHARMM36 generate secondary structures that are most consistent with protein structural data and sample the largest conformational space. The ion distribution and radius of gyration of the capsid are similar across all force fields investigated.

We developed recently [A. Fert\'e, et al., J. Phys. Chem. Lett. 11, 4359 (2020)] a method to compute single site double core hole (ssDCH or K$^{-2}$) spectra. We refer to that method as NOTA+CIPSI. In the present paper this method is applied to the O K$^{-2}$ spectrum of the CO$_2$ molecule, and we use this as an example to discuss in detail its convergence properties. Using this approach, a theoretical spectra in excellent agreement with the experimental one is obtained. Thanks to a thorough interpretation of the shake-up states responsible for the main satellite peaks and with the help of a comparison with the O K$^{-2}$ spectrum of CO, we can highlight the clear signature of the two non equivalent carbon oxygen bonds in the oxygen ssDCH CO$_2$ dication., Comment: 16 pages, 7 figures, 7 tables

Rotational spectroscopy and quantum mechanical calculations reveal a significant change in conformational landscapes when oxygen is substituted with sulfur: observation of features from nine conformers of diallylether versus one of the sulfide.

Magnetically induced ring currents are calculated from the magnetic shielding tensor by employing the Ampere-Maxwell law. The feasibility of the method is demonstrated by integrating the zz component of the shielding tensor along the symmetry axis of highly symmetric ring-shaped aromatic, antiaromatic and nonaromatic molecules. The calculated ring-current strengths agree perfectly with the ones obtained by integrating the current-density flux passing through a plane cutting half the molecular ring. The method can be used in combination with all electronic structure codes capable of calculating nuclear magnetic resonance (NMR) shielding tensors in general points in space. We also show that nucleus independent chemical shifts (NICS) along the symmetry axis are related to the spatial derivative of the strength of the global ring-current along the z axis.

Detection of nascent O($^3P_j$, $j=2,1,0$) atoms using one-photon resonant excitation to the $3s\,^3S^o_1$ state at $\sim 130$ nm followed by near-threshold ionization, i. e., 1 + 1' resonance enhanced multi-photon ionization (REMPI), has been investigated. The aim was to achieve low ion recoil, improved sensitivity, and reliable angular momentum polarization information, with an as simple as possible laser setup. An efficient 1 + 1' scheme has been found where the VUV light for the first step 1 is generated by difference frequency ($2\omega_1 - \omega_2$) VUV generation by four wave mixing in Kr gas, and the ionization step 1' uses 2$\omega_2$ at 289 nm. The presented scheme induces 9 m/s recoil of the O$^+$ ion using a two-dye laser system, and zero recoil should be possible by generating 302 nm radiation with a third dye laser. While this approach is much more sensitive than a previous 1 + 1' scheme using 212.6 nm for the 1' step, we found that the relatively intense 289 nm radiation does not saturate the 1' step. In order to test the ability of this scheme to accurately determine branching ratios, fine structure yields, and angular distributions including polarization information, it has been applied to O$_2$ photodissociation around 130 nm with subsequent O($^3P_j$) fragment detection.

We investigate the relationships between electron-density and electronic-energy errors produced by modern exchange-correlation density-functional approximations belonging to all of the rungs of Perdew’s ladder. To this aim, a panel of relevant (semi)local properties evaluated at critical points of the electron-density field (as defined within the framework of Bader’s atoms-in-molecules theory) are computed on a large selection of molecular systems involved in thermodynamic, kinetic, and noncovalent interaction chemical databases using density functionals developed in a nonempirical and minimally and highly parametrized fashion. The comparison of their density- and energy-based performance, also discussed in terms of density-driven errors, casts light on the strengths and weaknesses of the most recent and efficient density-functional approximations. E.B. and V.T. gratefully acknowledge GDR 3333 RFCT CNRS for their financial support through the call for proposals “Soutien á des collaborations scientifiques”. E.B. thanks ANR (Agence Nationale de la Recherche) and CGI (Commissariat á l’Investissement d’Avenir) for their financial support of this work through Labex SEAM (Science and Engineering for Advanced Materials and devices) ANR-10-LABX-096 and ANR-18-IDEX-0001. V.T. and L.J. thank the Labex SynOrg (ANR-11-2ABX-0029) for funding. The authors acknowledge the GENCI-CINES and the CRIANN centers for HPC resources (Projects A0080810359 and A0100810359) just like the local P3MB HPC platform of Université de Paris (ANR-18-IDEX-0001).

While the square root of Dirac’s $$\delta$$ δ is not defined in any standard mathematical formalism, postulating its existence with some further assumptions defines a generalized function called $$\gamma (x)$$ γ ( x ) which permits a quasi-classical treatment of simple systems like the H atom or the 1D harmonic oscillator for which accurate quantum mechanical energies were previously reported. The so-defined $$\gamma (x)$$ γ ( x ) is neither a traditional function nor a distribution, and it remains to be seen that any consistent mathematical approaches can be set up to deal with it rigorously. A straightforward use of $$\gamma (x)$$ γ ( x ) generates several paradoxical situations which are collected here. The help of the scientific community is sought to resolve these paradoxa.

Entropy benchmarking of different sized molecules in aqueous phase is carried out for known solvation models, where we compare geometry and solvation cavity packing parameters, which allows us to improve the accuracy of the obtained entropy values using empirical corrections. A comparison of solvation entropy models is conducted for a benchmarking set of 56 molecules, showing how an accurate description of cavitation entropy and its hindrance on other entropy values is important for large-sized solute molecules. Finally, we compare reaction free energies with entropies calculated using the most accurate solvation model considered, where we demonstrate a significant improvement in the accuracy relative to experimental values.

The electrostatic interaction of RNA with its aqueous environment is most relevant for defining macromolecular structure and biological function. The attractive interaction of phosphate groups in the RNA backbone with ions in the water environment leads to the accumulation of positively charged ions in the first few hydration layers around RNA. Electrostatics of this ion atmosphere and the resulting ion concentration profiles have been described by solutions of the nonlinear Poisson-Boltzmann equation and atomistic molecular dynamics (MD) simulations. Much less is known on contact pairs of RNA phosphate groups with ions at the RNA surface, regarding their abundance, molecular geometry, and role in defining RNA structure. Here, we present a combined theoretical and experimental study of interactions of a short RNA duplex with magnesium (Mg2+) ions. MD simulations covering a microsecond time range give detailed hydration geometries as well as electrostatics and spatial arrangements of phosphate-Mg2+ pairs, including both pairs in direct contact and separated by a single water layer. The theoretical predictions are benchmarked by linear infrared absorption and nonlinear two-dimensional infrared (2D-IR) spectra of the asymmetric phosphate stretch vibration which probes both local interaction geometries and electric fields. Contact pairs of phosphate groups and Mg2+ ions are identified via their impact on the vibrational frequency position and line shape. A quantitative analysis of infrared spectra for a range of Mg2+ excess concentrations and comparison with fluorescence titration measurements shows that on average 20 to 30% of the Mg2+ ions interacting with the RNA duplex form contact pairs. The experimental and MD results are in good agreement. In contrast, calculations based on the nonlinear Poisson-Boltzmann equation fail in describing the ion arrangement, molecular electrostatic potential and local electric field strengths correctly. Our results underline the importance of local electric field mapping and molecular-level simulations to correctly account for the electrostatics at the RNA-water interface.

In a quantum universe with a strong arrow of time, we postulate a low-entropy boundary condition (the Past Hypothesis) to account for the temporal asymmetry. In this paper, I show that the Past Hypothesis also contains enough information to simplify the quantum ontology and define a natural initial condition. First, I introduce Density Matrix Realism, the thesis that the quantum state of the universe is objective and impure. This stands in sharp contrast to Wave Function Realism, the thesis that the quantum state of the universe is objective and pure. Second, I suggest that the Past Hypothesis is sufficient to determine a natural density matrix, which is simple and unique. This is achieved by what I call the Initial Projection Hypothesis: the initial density matrix of the universe is the (normalized) projection onto the Past Hypothesis subspace (in the Hilbert space). Third, because the initial quantum state is unique and simple, we have a strong case for the Nomological Thesis: the initial quantum state of the universe is on a par with laws of nature. This new package of ideas has several interesting implications, including on the harmony between statistical mechanics and quantum mechanics, theoretical unity of the universe and the subsystems, and the alleged conflict between Humean supervenience and quantum entanglement., Minor changes to conform to the published version

Liquid–liquid phase-separated (LLPS) aerosol particles are known to exhibit increased cloud condensation nuclei (CCN) activity compared to well-mixed ones due to a complex effect of low surface tension and non-ideal mixing. The relation between the two contributions as well as the molecular-scale mechanism of water uptake in the presence of an internal interface within the particle is to date not fully understood. Here we attempt to gain understanding in these aspects through steered molecular dynamics simulation studies of water uptake by a vapor–hydroxy-cis-pinonic acid–water double interfacial system at 200 and 300 K. Simulated free-energy profiles are used to map the water uptake mechanism and are separated into energetic and entropic contributions to highlight its main thermodynamic driving forces. Atmospheric implications are discussed in terms of gas–particle partitioning, intraparticle water redistribution timescales and water vapor equilibrium saturation ratios. Our simulations reveal a strongly temperature-dependent water uptake mechanism, whose most prominent features are determined by local extrema in conformational and orientational entropies near the organic–water interface. This results in a low core uptake coefficient (ko/w=0.03) and a concentration gradient of water in the organic shell at the higher temperature, while entropic effects are negligible at 200 K due to the association-entropic-term reduction in the free-energy profiles. The concentration gradient, which results from non-ideal mixing – and is a major factor in increasing LLPS CCN activity – is responsible for maintaining liquid–liquid phase separation and low surface tension even at very high relative humidities, thus reducing critical supersaturations. Thermodynamic driving forces are rationalized to be generalizable across different compositions. The conditions under which single uptake coefficients can be used to describe growth kinetics as a function of temperature in LLPS particles are described.

Polymer self-consistent field theory techniques are used to derive quantum density functional theory without the use of the theorems of density functional theory. Instead, a free energy is obtained from a partition function that is constructed directly from a Hamiltonian, so that the results are, in principle, valid at finite temperatures. The main governing equations are found to be a set of modified diffusion equations, and the set of self-consistent equations are essentially identical to those of a ring polymer system. The equations are shown to be equivalent to Kohn-Sham density functional theory, and to reduce to classical density functional theory, each under appropriate conditions. The obtained non-interacting kinetic energy functional is, in principle, exact, but suffers from the usual orbital-free approximation of the Pauli exclusion principle in additional to the exchange-correlation approximation. The equations are solved using the spectral method of polymer self-consistent field theory, which allows the set of modified diffusion equations to be evaluated for the same computational cost as solving a single diffusion equation. A simple exchange-correlation functional is chosen, together with a shell-structure-based Pauli potential, in order to compare the ensemble average electron densities of several isolated atom systems to known literature results. The agreement is excellent, justifying the alternative formalism and numerical method. Some speculation is provided on considering the time-like parameter in the diffusion equations, which is related to temperature, as having dimensional significance, and thus picturing point-like quantum particles instead as non-local, polymer-like, threads in a higher dimensional thermal-space. A consideration of the double-slit experiment from this point of view is speculated to provide results equivalent to the Copenhagen interpretation., 32 pages, 5 figures

Neon cluster ions Ne$_s^+$ grown in pre-ionized, mass-to-charge selected helium nanodroplets (HNDs) reveal a strong enrichment of the heavy isotope $^{22}$Ne that depends on cluster size s and the experimental conditions. For small sizes the enrichment is much larger than previously reported for bare neon clusters grown in nozzle expansions and subsequently ionized. The enrichment is traced to the massive evaporation of neon atoms in a collision cell that is used to strip helium from the HNDs. We derive a relation between the enrichment of $^{22}$Ne in the cluster ion and its corresponding depletion factor $F$ in the vapor phase. The value thus found for $F$ is in excellent agreement with a theoretical expression that relates isotopic fractionation in two-phase equilibria of atomic gases to the Debye temperature. Furthermore, the difference in zero-point energies between the two isotopes computed from F agrees reasonably well with theoretical studies of neon cluster ions that include nuclear quantum effects in the harmonic approximation. Another fitting parameter provides an estimate for the size s$_i$ of the precursor of the observed Ne$_s^+$. The value is in satisfactory agreement with the size estimated by modeling the growth of Ne$_s^+$, and with lower and upper limits deduced from other experimental data. On the other hand, neon clusters grown in neutral HNDs that are subsequently ionized by electron bombardment exhibit no statistically significant isotope enrichment at all. The finding suggests that the extent of ionization-induced dissociation of clusters embedded in HNDs is considerably smaller than for bare clusters., 14 pages, 5 figures, supplementary material

High-resolution mass spectra of helium droplets doped with gold and ionized by electrons reveal He$_n$Au$^+$ cluster ions. Additional doping with heavy noble gases results in NenAu+, Ar$_n$Au$^+$, Kr$_n$Au$^+$, and Xe$_n$Au$^+$ cluster ions. The high stability predicted for covalently bonded Ar$_2$Au$^+$, Kr$_2$Au$^+$, and Xe$_2$Au$^+$ is reflected in their relatively high abundance. Surprisingly, the abundance of Ne$_2$Au$^+$ which is predicted to have zero covalent bonding character and no enhanced stability features a local maximum, too. The predicted size and structure of complete solvation shells surrounding ions with essentially non-directional bonding depends primarily on the ratio $\sigma$* of the ion-ligand $versus$ the ligand-ligand distance. For Au$^+$ solvated in helium and neon the ratio $\sigma$* is slightly below 1, favoring icosahedral packing in agreement with a maximum observed in the corresponding abundance distributions at $n$ = 12. He$_n$Au$^+$ appears to adopt two additional solvation shells of $I_h$ symmetry, containing 20 and 12 atoms, respectively. For Ar$_n$Au$^+$, with $\sigma$* $\approx$ 0.67, one would expect a solvation shell of octahedral symmetry, in agreement with an enhanced ion abundance at $n$ = 6. Another anomaly in the ion abundance at Ar$_9$Au$^+$ matches a local maximum in its computed dissociation energy.

Mismatched base pairs alter the flexibility and intrinsic curvature of DNA. The role of such DNA features is not fully understood in the mismatch repair pathway. MutS/DNA complexes exhibit DNA bending, PHE intercalation, and changes of base-pair parameters near the mismatch. Recently, we have shown that base-pair opening in the absence of MutS can discriminate mismatches from canonical base pairs better than DNA bending. However, DNA bending in the absence of MutS was found to be rather challenging to describe correctly. Here, we present a computational study on the DNA bending of canonical and G/T mismatched DNAs. Five types of geometric parameters covering template-based bending toward the experimental DNA structure, global, and local geometry parameters were employed in biased molecular dynamics in the absence of MutS. None of these parameters showed higher discrimination than the base-pair opening. Only roll could induce a sharply localized bending of DNA as observed in the experimental MutS/DNA structure. Further, we demonstrated that the intercalation of benzene mimicking PHE decreases the energetic cost of DNA bending without any effect on mismatch discrimination.

The rheology of suspensions showing discontinuous shear thickening (DST) is well documented in conventional rheometer with rotating tools, but their study in capillary flow is still lacking. We present results obtained in a homemade capillary rheometer working in an imposed pressure regime. We show that the shape of the experimental curve giving the volume flow rate versus the wall stress in a capillary can be qualitatively reproduced from the curve obtained in rotational geometry at imposed stress but instead of a sharp decrease of the volume flow rate observed at a critical stress, this transposition predicts a progressive decrease in flow rate. The Wyart-Cates theory is used to reproduce the stress-shear rate curve obtained in rotational geometry and then applied to predict the volume flow rate at imposed pressure. The theoretical curve predicts a total stop of the flow at high stress, whereas experimentally it remains constant. We propose a modification of the theory which, by taking into account the relaxation of the frictional contacts in the absence of shear rate, well predicts the high stress behavior. We also hypothesized that the DST transition propagates immediately inside the capillary, once the wall shear stress has reached its critical value: $\tau_R=\tau_c$, even if the internal shear stress $\tau(r, Comment: Rheologica Acta, Springer Verlag, 2021

The chemi-ionization of Ar, Kr, N2, H2, and D2 by Ne(3P2) and of Ar, Kr, and N2 by He(3S1) was studied by electron velocity map imaging (e-VMI) in a crossed molecular beam experiment. A curved magnetic hexapole was used to state-select the metastable species. Collision energies of 60 meV were obtained by individually controlling the beam velocities of both reactants. The chemi-ionization of atoms and molecules can proceed along different channels, among them Penning ionization and associative ionization. The evolution of the reaction is influenced by the internal redistribution of energy, which happens at the first reaction step that involves the emission of an electron. We designed and built an e-VMI spectrometer in order to investigate the electron kinetic energy distribution, which is related to the internal state distribution of the ionic reaction products. The analysis of the electron kinetic energy distributions allows an estimation of the ratio between the two-reaction channel Penning and associative ionization. In the molecular cases the vibrational or electronic excitation enhanced the conversion of internal energy into the translational energy of the forming ions, thus influencing the reaction outcome.

International audience; We report on high-dimensional quantum dynamical simulations of electron−hole separation in self-assembled mesomorphic nanostructures composed of donor−acceptor conjugated co-oligomers. The latter are based on perylene diimide (PDI) acceptor units combined with fluorene-thiophene-benzothiadiazole donor units, which form highly ordered, stacked structural motifs upon self-assembly. Simulations are shown for a first-principles parametrized model lattice of 25 stacked PDI units under the effects of an applied external field and temperature. The simulations are carried out with the multilayer multiconfiguration timedependent Hartree (ML-MCTDH) method with nearly 900 vibrational degrees of freedom and 25 electronic states. Temperature effects are included using the thermofield dynamics approach. A transition between a short-time coherent dynamics and a kinetic regime is highlighted. From a flux-overpopulation analysis, electron−hole dissociation rates are obtained in the range of 5−20 ns −1 in the absence of static disorder, exhibiting a moderate field and temperature dependence. These results for electron−hole separation rates can be employed as a benchmark to calibrate the parametrization of kinetic Monte Carlo simulations applied to much larger lattice sizes.

We introduce a new algorithm for the construction of the two-electron contributions to the Fock matrix in multilevel Hartree–Fock (MLHF) theory. In MLHF, the density of an active molecular region is optimized, while the density of an inactive region is fixed. The MLHF equations are solved in a reduced molecular orbital (MO) basis localized to the active region. The locality of the MOs can be exploited to reduce the computational cost of the Fock matrix: the cost related to the inactive density becomes linear scaling, while the iterative cost related to the active density is independent of the system size. We demonstrate the performance of this new algorithm on a variety of systems, including amino acid chains, water clusters, and solvated systems.

The lone-pair…π (lp…π) (deoxy)ribose…nucleobase stacking is a recurring structural motif in Z DNA and RNAs that is characterized by sub-van der Waals lp…π contacts (

This paper systematically examines the performance of contemporary wavefunction and density functional theory methods to identify robust and cost-efficient methods for predicting gas-phase anion binding energies. This includes the local coupled cluster LNO-CCSD(T) and DLPNO-CCSD(T), as well as double-hybrid DSD-PBEP86-D3(BJ) and various hybrid functionals M06-2X, B3LYP-D3(BJ), ωB97M-V, and ωB97X-V. The focus is on dual-hydrogen-bonding anion receptors that are commonly found in supramolecular chemistry and organocatalysis, namely, (thio)ureas, deltamides, (thio)squaramides, and croconamides as well as the yet-to-be-explored rhodizonamides. Of the methods examined, M06-2X emerged as the overall best performing method as the other functionals including DSD-PBEP86-D3(BJ) and the local coupled cluster DLPNO-CCSD(T) method displayed systematic errors that increase with the degree of carbonylation of the receptors. Hybrid ONIOM models that employed semiempirical methods (PM7, GFN1-xTB, and GFN2-xTB) and "threefold"-corrected small-basis set potentials (HF-3c, B97-3c, and PBEh-3c) were explored, and the best models resulted in 50- to 500-fold reduction in CPU time compared to W1-local. These calculations provide important insight into the structure-binding relationships where there is a direct correlation between Brønsted acidity and anion binding affinity, though the strength of the correlation also depends on other factors such as hydrogen-bonding geometry and the geometrical distortion that the receptor needs to undergo to bind the anion.

We applied relativistic multiconfigurational all-electron ab initio calculations including the spin–orbit interaction to calculate the 3d4f resonant inelastic X-ray scattering (RIXS) map (3d3/2 → 5f5/2 U M4 absorption edge and 4f5/2 → 3d3/2 U Mβ emission) of uranyl (UO22+). The calculated data are in excellent agreement with experimental results and allow a detailed understanding of the observed features and an unambiguous assignment of all involved intermediate and final states. The energies corresponding to the maxima of the resonant emission and the non-resonant (normal) emission were determined with high accuracy, and the corresponding X-ray absorption near edge structure spectra extracted at these two positions were simulated and agree well with the measured data. With the high quality of our theoretical data, we show that the cause of the splitting of the three main peaks in emission is due to the fine structure splitting of the 4f orbitals induced through the trans di-oxo bonds in uranyl and that we are able to obtain direct information about the energy differences between the 5f and 4f orbitals: Δ5f δ/ϕ – 4f δ/ϕ, Δ5f π* – 4f π, and Δ5f σ* – 4f σ from the 3d4f RIXS map. RIXS maps contain a wealth of information, and ab initio calculations facilitate an understanding of their complex structure in a clear and transparent way. With these calculations, we show that the multiconfigurational protocol, which is nowadays applied as a standard tool to study the X-ray spectra of transition metal complexes, can be extended to the calculation of RIXS maps of systems containing actinides., We show that the protocol based on relativistic multiconfigurational ab initio calculations, which is nowadays applied as a standard tool to study the X-ray spectra of transition metal complexes can be extended to actinide compounds. The excellent agreement with the measurements shows that the approach using the RASSCF/RASPT2 methods followed by the inclusion of spin−orbit coupling is applicable for the accurate calculation of 3d4f RIXS maps and reproduces the multiplet structure of the uranyl spectra very well.

We employ the Stroh octet formalism to develop a real-form expression of the Coulomb force acting on a line charge in an anisotropic piezoelectric bimaterial. The Coulomb force is derived using two different approaches and is expressed in terms of the generalized Barnett–Lothe tensors for the two piezoelectric half-spaces. Interestingly, we find that the Coulomb force is independent of the orientation of the bimaterial interface provided that the interface is parallel to the $$x_{3}$$ -axis and the distance between the charge and the interface remains unchanged. The Coulomb force on a line charge in a piezoelectric half-space with a rigid conducting surface or a traction-free insulating surface is deduced from the Coulomb force for two jointed piezoelectric half-spaces. In the case of a rigid conducting surface, we find that the Coulomb force always tends to attract the line charge to the surface. This is in contract to the case of a traction-free insulating surface for which we find that the Coulomb force can be either repulsive or attractive due to the piezoelectric effect.

Dissociation of a ligand isoniazid from a protein catalase was investigated using all-atom molecular dynamics (MD) simulations. Random acceleration MD (τ-RAMD) was used, in which a random artificial force applied to the ligand facilitates its dissociation. We have suggested a novel approach to extrapolate such obtained dissociation times to the zero-force limit assuming never before attempted universal exponential dependence of the bond strength on the applied force, allowing direct comparison with experimentally measured values. We have found that our calculated dissociation time was equal to 36.1 s with statistically significant values distributed in the interval of 0.2-72.0 s, which quantitatively matches the experimental value of 50 ± 8 s despite the extrapolation over 9 orders of magnitude in time.

Cannabicitran is an important cannabinoid natural product produced by Cannabis sativa and is often found at surprisingly high levels (up to ~10%) in "purified" commercial cannabidiol (CBD) extract preparations. Despite the prevalence of this molecule in CBD oil and other cannabinoid-related products, and the rapidly expanding interest in cannabinoids for treatment of a wide range of physiological conditions, only unassigned 1 H NMR data and partial unambiguous 13 C assignments have been published. Herein we report the complete 1 H and 13 C NMR assignments of cannabicitran and comparatively evaluate the performance of several DFT methods with varying levels of theory for the calculation of NMR chemical shifts.

Standard enthalpies, entropies, and heat capacities are calculated for 16,813 halocarbons using an automated high-fidelity thermochemistry workflow. This workflow generates conformers at density functional tight binding (DFTB) level, optimizes geometries, calculates harmonic frequencies, and performs 1D hindered rotor scans at DFT level, and computes electronic energies at G4 level. The computed enthalpies of formation for 400 molecules show good agreement with literature references, but the majority of the calculated species have no reference in the literature. Thus, this work presents the most accurate thermochemistry for many halocarbons to date. This new data set is used to train an extensive ensemble of group additivity values and hydrogen bond increment groups within the Reaction Mechanism Generator (RMG) framework. On average, the new group values estimate standard enthalpies for halogenated hydrocarbons within 3 kcal/mol of their G4 values. A significant contribution towards automated mechanism generation of halocarbon combustion, this research provides thermochemical data for thousands of novel halogenated species and presents a self-consistent set of halogen group additivity values.

Enhanced sampling and free energy calculation algorithms of the Thermodynamic Integration family (such as the Adaptive Biasing Force method, ABF) are not based on the direct computation of a free energy surface, but rather of its gradient. Integrating the free energy surface is non-trivial in dimension higher than one. Here the author introduces a flexible, portable implementation of a Poisson equation formalism to integrate free energy surfaces from estimated gradients in dimension 2 and 3, using any combination of periodic and non-periodic (Neumann) boundary conditions. The algorithm is implemented in portable C++, and provided as a standalone tool that can be used to integrate multidimensional gradient fields estimated on a grid using any algorithm, such as Umbrella Integration as a post-treatment of Umbrella Sampling simulations. It is also included in the implementation of ABF (and its extended-system variant eABF) in the Collective Variables Module, enabling the seamless computation of multidimensional free energy surfaces within ABF and eABF simulations. A Python-based analysis toolchain is provided to easily plot and analyze multidimensional ABF simulation results, including metrics to assess their convergence. The Poisson integration algorithm can also be used to perform Helmholtz decomposition of noisy gradients estimates on the fly, resulting in an efficient implementation of the projected ABF (pABF) method proposed by Leli\`evre and co-workers. In numerical tests, pABF is found to lead to faster convergence with respect to ABF in simple cases of low intrinsic dimension, but seems detrimental to convergence in a more realistic case involving degenerate coordinates and hidden barriers, due to slower exploration. This suggests that variance reduction schemes do not always yield convergence improvements when applied to enhanced sampling methods., Comment: 25 pages, 6 figures

21 p.-14 fig. In Memoriam Prof. Kilian Muñiz (R.I.P.). Excellent person, great heart., The innate immunity TLR4/MD-2 system is a membrane receptor of paramount importance as therapeutic target. Its assembly, upon binding of Gram-negative bacteria lipopolysaccharide (LPS), and also dependent on the membrane composition, finally triggers the immune response cascade. We here combine ab-initio calculations, molecular docking, all-atom molecular dynamics simulations, and thermodynamics calculations to provide the most realistic and complete 3D models of the active full TLR4 complex embedded into a realistic membrane to date. Our studies reveal functional and structural insights into the transmembrane domain behavior in different membrane environments, the ectodomain bouncing movement, and the dimerization patterns of the intracellular TIR domain. Our work provides TLR4 models as reasonable 3D structures for the (TLR4/MD-2/LPS) 2 architecture accounting for the active (agonist) state of the TLR4, and pointing to a signal transduction mechanism across cell membrane. These observations unveil relevant molecular aspects involved in the TLR4 innate immune pathways and will promote the discovery of new TLR4 modulators., This work was financially supported by the Spanish Ministry for Science and Innovation (grants CTQ2014-57141-R, CTQ2017-88353-R, and PID2020-113588RB-I00; grants BES-2012-053653 for L.P.R., BES-2015-071588 for J.G.C. and PRE2018-086249 for A.M.R.), and the European Commission Marie Sklodowska-Curie actions (H2020-MSCA-ITN 642157 “TOLLerant”).

The Na+-translocating NADH:quinone oxidoreductase (Na+-NQR) is the major Na+ pump in aerobic pathogens such as Vibrio cholerae. The interface between two of the NQR subunits, NqrB and NqrD, has been proposed to harbor a binding site for inhibitors of Na+-NQR. While the mechanisms underlying Na+-NQR function and inhibition remain underinvestigated, their clarification would facilitate the design of compounds suitable for clinical use against pathogens containing Na+-NQR. An in silico model of the NqrB–D interface suitable for use in molecular dynamics simulations was successfully constructed. A combination of algorithmic and manual methods was used to reconstruct portions of the two subunits unresolved in the published crystal structure and validate the resulting structure. Hardware and software optimizations that improved the efficiency of the simulation were considered and tested. The geometry of the reconstructed complex compared favorably to the published V. cholerae Na+-NQR crystal structure. Results from one 1 µs, three 150 ns and two 50 ns molecular dynamics simulations illustrated the stability of the system and defined the limitations of this model. When placed in a lipid bilayer under periodic boundary conditions, the reconstructed complex was completely stable for at least 1 µs. However, the NqrB–D interface underwent a non-physiological transition after 350 ns.

Quinonoid compounds play central roles as redox-active agents in photosynthesis and respiration and are also promising replacements for inorganic materials currently used in batteries. To design new quinonoid compounds and predict their state of protonation and redox behavior under various conditions, their pKa values must be known. Methods that can predict the pKa values of simple phenols cannot reliably handle complex analogues in which multiple OH groups are present and may form intramolecular hydrogen bonds. We have therefore developed a straightforward method based on a linear relationship between experimental pKa values and calculated differences in energy between quinols and their deprotonated forms. Simple adjustments allow reliable predictions of pKa values when intramolecular hydrogen bonds are present. Our approach has been validated by showing that predicted and experimental values for over 100 quinols and related compounds differ by an average of only 0.3 units. This accuracy makes it possible to select proper pKa values when experimental data vary, predict the acidity of quinols and related compounds before they are made, and determine the sites and orders of deprotonation in complex structures with multiple OH groups.

The Hessian matrix of the potential energy of molecular systems is employed not only in geometry optimizations or high-order molecular dynamics integrators but also in many other molecular procedures, such as instantaneous normal mode analysis, force field construction, instanton calculations, and semiclassical initial value representation molecular dynamics, to name a few. Here, we present an algorithm for the calculation of the approximated Hessian in molecular dynamics. The algorithm belongs to the family of unsupervised machine learning methods, and it is based on the neural gas idea, where neurons are molecular configurations whose Hessians are adopted for groups of molecular dynamics configurations with similar geometries. The method is tested on several molecular systems of different dimensionalities both in terms of accuracy and computational time versus calculating the Hessian matrix at each time-step, that is, without any approximation, and other Hessian approximation schemes. Finally, the method is applied to the on-the-fly, full-dimensional simulation of a small synthetic peptide (the 46 atom N-acetyl-l-phenylalaninyl-l-methionine amide) at the level of DFT-B3LYP-D/6-31G* theory, from which the semiclassical vibrational power spectrum is calculated.

Atomistic models provide a detailed representation of molecular systems, but are sometimes inadequate for simulations of large systems over long timescales. Coarse-grained models enable accelerated simulations by reducing the number of degrees of freedom, at the cost of reduced accuracy. New optimisation processes to parameterise these models could improve their quality and range of applicability. We present an automated approach for the optimisation of coarse-grained force fields, by reproducing free energy data derived from atomistic molecular simulations. To illustrate the approach, we implemented hydration free energy gradients as a new target for force field optimisation in ForceBalance and applied it successfully to optimise the un-charged side-chains and the protein backbone in the SIRAH protein coarse-grain force field. The optimised parameters closely reproduced hydration free energies of atomistic models and gave improved agreement with experiment., New parameterisation processes for coarse-grained models can improve their quality and range of applicability. We present an automated approach for the optimisation of a coarse-grained protein force field using free energy gradients as a new target.

We propose to analyze molecular dynamics (MD) output via a supervised machine learning (ML) algorithm, the decision tree. The approach aims to identify the predominant geometric features which correlate with trajectories that transition between two arbitrarily defined states. The data-driven algorithm aims to identify these features without the bias of human “chemical intuition”. We demonstrate the method by analyzing the proton exchange reactions in formic acid solvated in small water clusters. The simulations were performed with ab initio MD combined with a method to efficiently sample the rare event, path sampling. Our ML analysis identified relevant geometric variables involved in the proton transfer reaction and how they may change as the number of solvating water molecules changes.

A recently developed lower bound theory for Coulombic problems (E. Pollak, R. Martinazzo, J. Chem. Theory Comput.2021, 17, 1535) is further developed and applied to the highly accurate calculation of the ground-state energy of two- (He, Li+, and H–) and three- (Li) electron atoms. The method has been implemented with explicitly correlated many-particle basis sets of Gaussian type, on the basis of the highly accurate (Ritz) upper bounds they can provide with relatively small numbers of functions. The use of explicitly correlated Gaussians is developed further for computing the variances, and the necessary modifications are here discussed. The computed lower bounds are of submilli-Hartree (parts per million relative) precision and for Li represent the best lower bounds ever obtained. Although not yet as accurate as the corresponding (Ritz) upper bounds, the computed bounds are orders of magnitude tighter than those obtained with other lower bound methods, thereby demonstrating that the proposed method is viable for lower bound calculations in quantum chemistry applications. Among several aspects, the optimization of the wave function is shown to play a key role for both the optimal solution of the lower bound problem and the internal check of the theory.

Vibrational spectroscopy is key for probing the interplay between the structure and dynamics of aqueous systems. In order to map different regions of experimental spectra to the microscopic structure of a system, it is important to combine them with first-principles atomistic simulations that incorporate the quantum nature of nuclei. Here, we show that the large cost of calculating quantum vibrational spectra of aqueous systems can be dramatically reduced compared to standard path integral methods by using approximate quantum dynamics based on high-order path integrals. Together with state-of-the-art machine-learned electronic properties, our approach gives an excellent description of the infrared and Raman spectra of bulk water, but also of 2D correlation and more challenging sum-frequency generation spectra of the water-air interface. This paves the way for understanding complex interfaces such as water encapsulated between or in contact with hydrophobic and hydrophilic materials, through robust and inexpensive surface sensitive and multidimensional spectra with first-principles accuracy., Comment: 7 pages, 4 figures

Relative binding free energy calculations in drug design are becoming a useful tool in facilitating lead binding affinity optimization in a cost- and time-efficient manner. However, they have been limited by technical challenges such as the manual creation of large numbers of input files to set up, run, and analyze free energy simulations. In this Application Note, we describe FEPrepare, a novel web-based tool, which automates the setup procedure for relative binding FEP calculations for the dual-topology scheme of NAMD, one of the major MD engines, using OPLS-AA force field topology and parameter files. FEPrepare provides the user with all necessary files needed to run a FEP/MD simulation with NAMD. FEPrepare can be accessed and used at https://feprepare.vi-seem.eu/.

Rate coefficients for the reaction of NO 3 radicals with a series of aromatic aldehydes were measured in a 7300 L simulation chamber at ambient temperature and pressure by relative and absolute methods. The rate coefficients for benzaldehyde (BA), ortho-tolualdehyde (O-TA), meta-tolualdehyde (M-TA), para-tolualdehyde (P-TA), 2,4-dimethyl benzaldehyde (2,4-DMBA), 2,5-dimethyl benzaldehyde (2,5-DMBA) and 3,5-dimethyl benzaldehyde (3,5-DMBA) were k1= 2.6 ± 0.3, k2= 8.7 ± 0.8, k3= 4.9 ± 0.5, k4= 4.9 ± 0.4, k5= 15.1 ± 1.3, k6= 12.8 ± 1.2 and k7= 6.2 ± 0.6, respectively, in the units of 10 −15 cm 3 molec. −1 s −1 at 298 ± 2 K. The rate coefficient k13 for the reaction of the NO 3 radical with deuterated benzaldehyde (benzaldehyde-d 1) was found to be half that of k1 . The end product of the reaction in an excess of NO 2 was measured to be C 6 H 5 C(O)O 2 NO 2 . Theoretical calculations of aldehydic bond energies and reaction pathways indicate that the NO 3 radical reacts primarily with aromatic aldehydes through the abstraction of an aldehydic hydrogen atom. The atmospheric implications of the measured rate coefficients are briefly discussed.

Ultrafast transient infrared (TRIR) spectroscopy is widely used to measure the excitation-induced structural changes of protein-bound chromophores. Here, we design a novel and general strategy to compute TRIR spectra of photoreceptors by combining μs-long MM molecular dynamics with ps-long QM/AMOEBA Born–Oppenheimer molecular dynamics (BOMD) trajectories for both ground and excited electronic states. As a proof of concept, the strategy is here applied to AppA, a blue-light-utilizing flavin (BLUF) protein, found in bacteria. We first analyzed the short-time evolution of the embedded flavin upon excitation revealing that its dynamic Stokes shift is ultrafast and mainly driven by the internal reorganization of the chromophore. A different normal-mode representation was needed to describe ground- and excited-state IR spectra. In this way, we could assign all of the bands observed in the measured transient spectrum. In particular, we could characterize the flavin isoalloxazine-ring region of the spectrum, for which a full and clear description was missing.

Understanding the lateral organization in plasma membranes remains an open problem and is of great interest to many researchers. Model membranes consisting of coexisting domains are commonly used as simplified models of plasma membranes. The coarse-grained (CG) Martini force field has successfully captured spontaneous separation of ternary membranes into a liquid-disordered and a liquid-ordered domain. With all-atom (AA) models, however, phase separation is much harder to achieve due to the slow underlying dynamics. To remedy this problem, here, we apply the virtual site (VS) hybrid method on a ternary membrane composed of saturated lipids, unsaturated lipids, and cholesterol to investigate the phase separation. The VS scheme couples the two membrane leaflets at CG and AA resolution. We found that the rapid phase separation reached by the CG leaflet can accelerate and guide this process in the AA leaflet.

The structural properties and radial distributions of the valence electron in different excited levels of Na atom (n = 3–5, l = 0–4; n and l being the principal and orbital angular momentum quantum numbers, respectively) under impenetrable spherical confinement have been studied, where the interaction between the frozen core and the valence electron is mimicked by a model potential available in the literature. The effect of the core on the valence electron has been investigated by estimating the structural properties of Na10+ ion under similar confinement. Scaled radial densities at the nucleus and related ratios are presented for a few excited states of the valence electron of Na atom and the corresponding analytic results have been tested numerically.

The nature of the bulk hydrated electron has been a challenge for both experiment and theory due to its short lifetime and high reactivity, and the need for a high-level of electronic structure theory to achieve predictive accuracy. The lack of a classical atomistic structural formula makes it exceedingly difficult to model the solvated electron using conventional empirical force fields, which describe the system in terms of interactions between point particles associated with atomic nuclei. Here we overcome this problem using a machine-learning model, that is sufficiently flexible to describe the effect of the excess electron on the structure of the surrounding water, without including the electron in the model explicitly. The resulting potential is not only able to reproduce the stable cavity structure but also recovers the correct localization dynamics that follow the injection of an electron in neat water. The machine learning model achieves the accuracy of the state-of-the-art correlated wave function method it is trained on. It is sufficiently inexpensive to afford a full quantum statistical and dynamical description and allows us to achieve accurate determination of the structure, diffusion mechanisms, and vibrational spectroscopy of the solvated electron., The nature of the bulk hydrated electron has been a challenge for both experiment and theory. Here the authors use a machine-learning model trained on MP2 data to achieve an accurate determination of the structure, diffusion mechanisms, and vibrational spectroscopy of the solvated electron.

Proteins can be targeted to organellar membranes using a tail anchor (TA), a stretch of hydrophobic amino acids found at the polypeptide carboxyl-terminus. The Fis1 protein (Fis1p), which promotes mitochondrial and peroxisomal division in the yeast Saccharomyces cerevisiae, is targeted to those organelles by its TA. Substantial evidence suggests that Fis1p insertion into the mitochondrial outer membrane can occur without the need for a translocation machinery. However, recent findings raise the possibility that Fis1p insertion into mitochondria might be promoted by a proteinaceous complex. Here, we have performed atomistic and coarse-grained simulations to analyze the adsorption, conformation and orientation of the Fis1(TA). Our results support stable insertion at the mitochondrial outer membrane in a monotopic, rather than a bitopic (transmembrane), configuration. Once inserted in the monotopic orientation, unassisted transition to the bitopic orientation is expected to be blocked by the highly charged nature of the TA carboxyl-terminus and by the Fis1p cytosolic domain. Our results are consistent with a model in which Fis1p does not require a translocation machinery for insertion at mitochondria.