Consistent buckling distortions of a large membrane patch (200 × 200 Å) are observed during molecular dynamics (MD) simulations using the Monte-Carlo (MC) barostat in combination with a hard Lennard-Jones (LJ) cutoff. The buckling behavior is independent of both the simulation engine and the force field but requires the MC barostat-hard LJ cutoff combination. Similar simulations of a smaller patch (90 × 90 Å) do not show buckling, but do show a small, systematic reduction in the surface area accompanied by ~1 Å thickening suggestive of compression. We show that a mismatch in the way potentials and forces are handled in the dynamical equations versus the MC barostat results in a compressive load on the membrane. Moreover, a straightforward application of elasticity theory reveals that a minimal compression of the linear dimensions of the membrane, inversely proportional to the edge length, is required for buckling, explaining this differential behavior. We recommend always using LJ force or potential-switching when the MC barostat is employed to avoid undesirable membrane deformations.

The Mukaiyama aldol reaction is a powerful tool for the construction of the carbon-carbon bond and the formation of β-hydroxycarbonyl compounds. In this work, the mechanism of acetaldehyde and 2-siloxy-1-propene both in the absence and presence of the catalyst BF3 was investigated based on density functional theory. The mechanism includes two major steps: the formation of the carbon-carbon bond and the removal of SiH3 /BF2 by water. The energy barrier of the carbon-carbon bond formation process in the presence of BF3 is obviously lower, indicating that BF3 is a good catalyst for this reaction. In terms of molecular configuration, the different tensions between the five-membered-ring and six-membered-ring can be considered as the possible reason for the catalytic effect of BF3 . In terms of charge transfer, the charges of natural population analysis in the carbon atom of the carbonyl group in acetaldehyde becomes more positive, which is easier to attack by nucleophiles and promote the nucleophilic process.

The adsorption of N-heterocyclic carbenes (NHCs) on Cu(111) and Au(111) surfaces is studied with density-functional theory. The role of the molecular side groups as well as the surface morphology in determining the adsorption geometry are explored in detail. Flat-laying NHCs, as observed experimentally for NHC with relatively small side groups, result from the adsorption at adatoms and give rise to the so-called ballbot configurations, which are more stable than adsorption on flat surfaces and provide an efficient precursor for the formation of bis(NHC) dimers. On Au(111), the resulting (NHC)2 Au complexes are purely physisorbed and thus mobile. On the more reactive Cu(111), in contrast, the central Cu atom in the (NHC)2 Cu dimer is still covalently bound to the surface, resulting in a mobility, which has to be thermally activated.

Dynamics of protein cavities associated with protein fluctuations and conformational plasticity is essential for their biological function. NMR ensembles, molecular dynamics (MD) simulations, and normal mode analysis (NMA) provide appropriate frameworks to explore functionally relevant protein dynamics and cavity changes relationships. Within this context, we have recently developed analysis of null areas (ANA), an efficient method to calculate cavity volumes. ANA is based on a combination of algorithms that guarantees its robustness against numerical differentiations. This is a unique feature with respect to other methods. Herein, we present an updated and improved version that expands it use to quantify changes in cavity features, like volume and flexibility, due to protein structural distortions performed on predefined biologically relevant directions, for example, directions of largest contribution to protein fluctuations (principal component analysis [PCA modes]) obtained by MD simulations or ensembles of NMR structures, collective NMA modes or any other direction of motion associated with specific conformational changes. A web page has been developed where its facilities are explained in detail. First, we show that ANA can be useful to explore gradual changes of cavity volume and flexibility associated with protein ligand binding. Secondly, we perform a comparison study of the extent of variability between protein backbone structural distortions, and changes in cavity volumes and flexibilities evaluated for an ensemble of NMR active and inactive conformers of the epidermal growth factor receptor structures. Finally, we compare changes in size and flexibility between sets of NMR structures for different homologous chains of dynein.

We carry out molecular dynamics simulations for pure liquid primary alcohols ranging from methanol to 1-decanol under ambient conditions. Based on the OPLS-AA force field with the L-OPLS correction, we demonstrate that a few % increases in the partial charges deliver the realistic dynamics (self-diffusion coefficient and shear viscosity) and structure (density and X-ray scattering intensity) as well as enthalpy of vaporization and isothermal compressibility. The validity against thermal expansion coefficient, isobaric heat capacity, and static dielectric constant are also discussed.

Maximum overlap methods are effective tools for optimizing challenging ground- and excited-state wave functions using self-consistent field models such as Hartree-Fock and Kohn-Sham density functional theory. Nevertheless, such models have shown significant sensitivity to the user-defined initial guess of the target wave function. In this work, a projection operator framework is defined and used to provide a metric for non-aufbau orbital selection in maximum-overlap-methods. The resulting algorithms, termed the Projection-based Maximum Overlap Method (PMOM) and Projection-based Initial Maximum Overlap Method (PIMOM), are shown to perform exceptionally well when using simple user-defined target solutions based on occupied/virtual molecular orbital permutations. This work also presents a new metric that provides a simple and conceptually convenient measure of agreement between the desired target and the current or final SCF results during a calculation employing a maximum-overlap method.

Transient absorption spectra (TAS) of lead halide perovskites can provide important insights into the nature of the photoexcited state dynamics of this prototypical class of materials. Here, we perform ground and excited state molecular dynamics (MD) simulations within a restricted open shell Kohn-Sham (ROKS) approach in order to interpret the characteristic features of the TAS of CsPbBr3 . Our results reveal that properties such as the finite temperature band gap, the Stokes shift, and therefore, also the TAS are strongly size-dependent. Our TAS simulations show an early positive red-shifted feature on the fs scale that can be explained by geometric relaxation in the excited state. As excited-state processes can crucially affect the electronic properties of this class of photoactive materials, our observations are an important ingredient for further optimization of lead halide based optoelectronic devices.

Accurate prediction of protein stability changes upon mutation (ΔΔG) is increasingly important to evolution studies, protein engineering, and screening of disease-causing gene variants but is challenged by biases in training data. We investigated 45 linear regression models trained on data sets that account systematically for destabilization bias and mutation-type bias BM . The models were externally validated on three test data sets probing different pathologies and for internal consistency (symmetry and neutrality). Model structure and performance substantially depended on training data and even fitting method. We developed two final models: SimBa-IB for typical natural mutations and SimBa-SYM for situations where stabilizing and destabilizing mutations occur to a similar extent. SimBa-SYM, despite is simplicity, is essentially non-biased (vs. the Ssym data set) while still performing well for all data sets (R ~ 0.46-0.54, MAE = 1.16-1.24 kcal/mol). The simple models provide advantage in terms of interpretability, use and future improvement, and are freely available on GitHub.

Thiophenols are chemical species with multiple desirable biological properties, including their primary and secondary antioxidant capacity. In this work, the repairing antioxidant activity of eight different thiophenols has been investigated for damaged leucine and tryptophane. The investigation was carried out employing quantum mechanical and transition state methods to calculate the thermodynamic and kinetic data of the reactions involved, while simulating the biological conditions at physiological pH and aqueous and lipidic medium. The analysis of the atomic charges and the spin densities at each of the points on the potential energy surface was the tool that allowed the elucidation of the reaction mechanisms through which thiophenols repair the oxidative damage caused to the amino acids leucine and tryptophan. It was found that thiophenols can repair leucine via a hydrogen atom transfer mechanism in a manner which is similar to the one used by glutathione to repair the carbon-centered radicals of guanosine. In addition, thiophenols can also restore tryptophane, a nitrogen-centered radical, via proton-coupled electron transfer and single electron transfer mechanisms. Moreover, both processes occur at close to diffusion-controlled rates.

The counterpoise (CP) correction by Boys and Bernardi has been well accepted as a reliable strategy to account for basis set superposition error (BSSE) in intermolecular complexes. The behavior of the CP correction was thoroughly studied in individual molecules of molecular complexes. This work studies the performance of the CP correction in many-body clusters including three-body clusters of organic compounds in the 3B-69 dataset. Additionally, we used crystal structures of polymorphs of benzene, aspirin, and oxalyl dihydrazide (ODH) to construct a many-body cluster dataset, abbreviated as the MBC-36 dataset, consisting of two, four and eight molecules, and 16 molecules in the case of benzene. A series of Dunning's basis sets-cc-pXZ and aug-cc-pXZ (X = D and T)-were used to predict CP-corrected Hartree-Fock (HF) interaction energies of the 3B-69 and MBC-36 datasets. The CP-corrected interaction energies were found to be basis-set independent, whereas the non-CP corrected interaction energies were found not to a follow a smooth exponential fitting as previously found for electronic energies of individual molecules. This observation was attributed to the presence of non-additive induction forces in some clusters. Two 2 × 2 × 2 supercells of benzene polymorphs were constructed to explore the local nature of BSSE effects. A cut-off radius of 10 Å was demonstrated to be sufficient to fully recover these effects. Although the behavior of CP correction was found to be non-conventional in many-body clusters of organic compounds, the use of a small basis set such as cc-pVDZ showed excellent performance in the prediction of HF interaction energies.

The powerful independent gradient model (IGM) method has been increasingly popular in visual analysis of intramolecular and intermolecular interactions in recent years. However, we frequently observed that there is an evident shortcoming of IGM map in graphically studying weak interactions, that is its isosurfaces are usually too bulgy; in these cases, not only the graphical effect is poor, but also the color on some areas on the isosurfaces is inappropriate and may lead to erroneous analysis conclusions. In addition, the IGM method was originally proposed based on promolecular density, which is quite crude and does not take actual electronic structure into account. In this article, we propose an improvement version of IGM, namely IGM based on Hirshfeld partition of molecular density (IGMH), which replaces the free-state atomic densities involved in the IGM method with the atomic densities derived by Hirshfeld partition of actual molecular electron density. This change makes IGM have more rigorous physical background. A large number of application examples in this article, including molecular and periodic systems, weak and chemical bond interactions, fully demonstrate the important value of IGMH in intuitively understanding interactions in chemical systems. Comparisons also showed that the IGMH usually has markedly better graphical effect than IGM and overcomes known problems in IGM. Currently IGMH analysis has been supported in our wavefunction analysis code Multiwfn (http://sobereva.com/multiwfn). We hope that IGMH will become a new useful method among chemists for exploring interactions in wide variety of chemical systems.

Motivated by recent experiments, the laser-induced alignment-and-orientation (A&O) dynamics of the prolate symmetric top CH3 X (X = F, Cl, Br, I) molecules is investigated, with particular emphasis on the effect of halogen substitution on the rotational constants, dipole moments, and polarizabilities of these species, as these quantities determine the A&O dynamics. Insight into possible control schemes for preferred A&O dynamics of halogenated molecules and best practices for A&O simulations are provided, as well. It is shown that for accurate A&O -dynamics simulations it is necessary to employ large basis sets and high levels of electron correlation when computing the rotational constants, dipole moments, and polarizabilities. The benchmark-quality values of these molecular parameters, corresponding to the equilibrium, as well as the vibrationally averaged structures are obtained with the help of the focal-point analysis (FPA) technique and explicit electronic-structure computations utilizing the gold-standard CCSD(T) approach, basis sets up to quintuple-zeta quality, core-correlation contributions and, in particular, relativistic effects for CH3 Br and CH3 I. It is shown that the different A&O behavior of the CH3 X molecules in the optical regime is mostly caused by the differences in their polarizability anisotropy, in other terms, the size of the halogen atom. In contrast, the A&O dynamics of the CH3 X series induced by an intense few-cycle THz pulse is mostly governed by changes in the rotational constants, due to the similar dipole moments of the CH3 X molecules. The A&O dynamics is most sensitive to the B rotational constant: even the difference between its equilibrium and vibrationally-averaged values results in noticeably different A&O dynamics. The contribution of rotational states having different symmetry, weighted by nuclear-spin statistics, to the A&O dynamics is also studied.

When the structures of 1342 molecules are optimized by 30 methods and 7 basis sets, there appear 289 (21.54%) problematic molecules and 112 (8.35%) failed ones. When 278 problematic molecules are compared, the best methods are BHandH and LC-wPBE, while B97D, BP86, HFS, VSXC, and HCTH are very unreliable. When 179 problematic molecules are computed with larger basis sets, the smallest mean absolute deviation (MAD) of bond angle (2.3°) is shown by QCISD(T)/cc-pVTZ, while the smallest MAD of bond length (0.021 Å), the best SUM1 (4.9 unit), and the best SUM2 (2.4 unit) are shown by DSDPBEP86(Full), DSDPBEP86, PBE1PBE-D3, MP2, and MP2(Full) in combination with aug-cc-pVQZ, cc-pVQZ, Def2QZVP, Def2TZVPP, and/or 6-311++G(3df,3pd). Very large basis sets, for example, larger than cc-pVTZ usually have to be used to obtain very good structures and the performances of many density-functional theory methods are encouraging. The best results may be the limit of modern computational chemistry.

Density functional theory (DFT) calculations have been performed to gain insight into the reaction mechanism of the Co(I)-catalyzed asymmetric [2 + 2] cycloaddition reaction of enyne 1a with ethylene 2 to give the functionalized cyclobutene E-4a possessing a chiral, all-carbon quaternary center in the ring framework (Science, 361, 68-72). This study reveals that the whole catalysis can be characterized via three stages: (i) oxidative dimerization followed by reductive elimination gives the intermediate IM3, (ii) the alkenyl-Co(III) metallacycloheptene IM6 formation with the addition of another equivalent ethylene via an oxidative dimerization process, (iii) β-Hydrogen elimination and reductive elimination from IM6 to result in the final product E-4a and regenerate the active speices IM1 for the next catalytic cycle. Each stage is kinetically and thermodynamically feasible for experimental realization under mild conditions, and the formation of the alkenyl-Co(III) metallacycloheptene IM6, with a barrier of 27.2 kcal mol-1 (i.e., IM2 → TS4), should be the rate-determining step (RDS) during the whole catalysis. In addition, the origins of enantioselectivity and regioselectivity of the product are discussed.

Rings are one of the major scaffold components of drugs in medicinal chemistry, due to their unique electronic distribution, scaffold rigidity, and three-dimensionality while lipophilicity is considered as a vital parameter of rings that can influence the reactivity, metabolic stability, and toxicity. We have analyzed the electronic features, hydration patterns, solvation effect and lipophilicity data for 51 most widely used ring systems in drugs. Molecular electrostatic potential (MESP) topology analysis has been used to assess the electronic distribution in rings which provided an easy interpretation of the most suitable hydration patterns of the ring with H2 O molecule. Further, the global minimum of ring…H2 O complex has been utilized to predict lipophilicity (logP) with the incorporation of implicit solvation effect. Classification of ring systems based on their molecular weight into four categories, viz. small ring 'sr', medium ring 'mr', large ring 'lr' and extra large ring 'xlr' systems has led to the finding of strong correlations between logP and hydration energy with R = 0.942, 0.933, 0.968 and 0.933, respectively. The micro solvation model is found to be useful for locating the hydrophobic-hydrophilic border for each category of rings in terms of hydration energy whereas the implicit solvation model used for two solvents, n-octanol and water on the most stable hydrated structure led to a global correlation between logP and solvation energy ratio. This correlation predicts a limiting logP value -7.03 for the most hydrophilic ring system and also suggests a clear partitioning of the ring molecules into hydrophobic and hydrophilic classes. The MESP topology-guided approach to understand the electronic features and hydration patterns of rings in drugs lead to powerful predictions on their lipophilicity behavior.

Five ionic liquids are selected for benchmarking the performance of quasi-harmonic density functional theory (DFT) calculations of structural, phonon, and thermodynamic properties of their crystals. Data predicted by individual computational setups are sorted, establishing a distinct hierarchy among the first-principles approaches. PBE-D3 and B3LYP-D3 functionals are coupled with various plane wave and Gaussian-type orbital (GTO) basis sets. Propagation of the basis set superposition error and of the imperfections of both functionals into finite-temperature properties is discussed in detail. PBE-D3 together with a triple-zeta GTO basis set often yields the most accurate predictions of predicted molar volume and heat capacity with errors at 1% and 8%, respectively, representing the state-of-the-art for quasi-harmonic DFT calculations for crystalline ionic liquids. Fortuitous error cancellation between the basis-set superposition (overbinding) and PBE imperfection (overexpanding) strongly affects the overall accuracy, unlike the case of B3LYP/GTO calculations, impeding systematic convergence of the methodology towards higher accuracy.

Clar's aromatic π -sextet rule is a widely used qualitative method for assessing the electronic structure of polycyclic benzenoid hydrocarbons. Unfortunately, many of the quantum chemical concordances for this rule have a limited range of applicability. Here, we show that the fundamental probabilities associated with a distribution of electrons over domain partitions support Clar's rule in both mean-field and static correlation regimes. In particular, domain partitions that maximize those probabilities reflect the dominance of Clar structures in the electronic structure of these molecules. These findings suggest that extending methods that aim to maximize probabilities by deforming domain partitions could lead to novel quantum chemical underpinnings for many chemical concepts.

The accurate ground-state potential energy functions of the beryllium lithium dimer, BeLi, and its cation, BeLi+ , have been determined from ab initio calculations using the multi-reference averaged coupled-pair functional (MR-ACPF) method in conjunction with the correlation-consistent core-valence basis sets up to septuple-zeta quality. The importance of the electron correlation beyond the MR-ACPF level of approximation, scalar relativistic, and adiabatic effects was discussed. For BeLi+ , the similar calculation was performed using the single-reference coupled-cluster method, up to the CCSDTQ level of approximation. The vibration-rotation energy levels of the two species were predicted to near the "spectroscopic" accuracy. Strangely enough, the predicted vibrational term values do not compare well with the recent experimental data for either BeLi or BeLi+ , with discrepancies reaching as much as 20-60 cm-1 for highly excited vibrational levels.