The frequent outbreaks of the AIDS (Acquired Immune Deficiency Syndrome) pandemic and the limited availability of anti-Human Immunodeficiency Virus (HIV) drugs highlight the urgent need to develop new antiviral drugs. A detailed understanding of the interactions between TAR-Binding Proteins (TBP) and RNA will facilitate the discovery of new anti-AIDS drugs. In order to characterize and explore the key interactions between RNA and TBP, we focused on the wild type (WT) and three mutant TBPs (TBP6.9, TBP6.7, and TBP6.3) with RNA, multiple molecular dynamics simulation and energy computation were performed. The results showed that 12 key residues played a major role in the interaction between TBP and RNA. The mutated residues of TBP changed the interaction between their surrounding residues and RNA, thus affecting the binding of TBP to RNA. In addition, structural and energy analyses showed that in contrast with WT TBP-RNA complex, the mutated residues had little effect on the backbone structure of TBP, but changes in the van der Waals interactions and electrostatic interaction associated with the side chains are responsible for the altered the binding between three mutant TBPs and RNA complexes. The discovery of TBP-RNA recognition mechanism in our work provides some useful insights and new opportunities for the development of anti-aids drugs.

The determination of gas phase thermochemical properties of per- and polyfluoroalkyl substances (PFAS) is central to understanding the long-range transport behavior of PFAS in the atmosphere. Prior gas-phase studies have reported the properties of perfluorinated sulfonic acid (PFOS) and perfluorinated octanoic acid (PFOA). Here, this study reports the gas phase enthalpies of formation of short- and long-chain PFAS and their precursor molecules determined using density functional theory (DFT) and ab initio approaches. Two density functionals, two ab initio methods and an empirical method were used to compute enthalpies of formation with the total atomization approach and an isogyric reaction. The performance of the computational methods employed in this work were validated against the experimental enthalpies of linear alkanoic acids and perfluoroalkanes. The gas-phase determinations will be useful for future studies of PFAS in the atmosphere, and the methodological choices will be helpful in the study of other PFAS.

Quantum chemical calculations were carried out to investigate the nature of the bonding between a neutral Be3 ring and noble gas atom. Electronic structure calculation for these complexes was carried out at different computational levels in association with natural bond orbital, quantum theory of atoms in molecules, electron localization function, symmetry adapted perturbation theory, and molecular electrostatic potential surface analysis of Be3 complexes. The Be atoms in the Be3 moiety are chemically bonded to one another, with the BeBe bond dissociation energy being ~125 kJ mol-1 . The Be3 ring interacts with the noble gases through non-covalent interactions. The binding energies of the noble gas atoms with the Be3 ring increases with increase in their atomic number. The non-covalent interaction index, density overlap region indicator and independent gradient model analyses reveal the presence of non-covalent inter-fragment interactions in the complexes. Energy decomposition analysis reveals that dispersion plays the major role towards stabilizing these systems.

We have quantum chemically studied the iron-mediated CX bond activation (X = H, Cl, CH3 ) by d8 -FeL4 complexes using relativistic density functional theory at ZORA-OPBE/TZ2P. We find that by either modulating the electronic effects of a generic iron-catalyst by a set of ligands, that is, CO, BF, PH3 , BN(CH3 )2 , or by manipulating structural effects through the introduction of bidentate ligands, that is, PH2 (CH2 )n PH2 with n = 6-1, one can significantly decrease the reaction barrier for the CX bond activation. The combination of both tuning handles causes a decrease of the CH activation barrier from 10.4 to 4.6 kcal mol-1 . Our activation strain and Kohn-Sham molecular orbital analyses reveal that the electronic tuning works via optimizing the catalyst-substrate interaction by introducing a strong second backdonation interaction (i.e., "ligand-assisted" interaction), while the mechanism for structural tuning is mainly caused by the reduction of the required activation strain because of the pre-distortion of the catalyst. In all, we present design principles for iron-based catalysts that mimic the favorable behavior of their well-known palladium analogs in the bond-activation step of cross-coupling reactions.

We present a toolkit that allows for the preparation of QM/MM input files from a conformational ensemble of molecular geometries. The package is currently compatible with trajectory and topology files in Amber, CHARMM, GROMACS and NAMD formats, and has the possibility to generate QM/MM input files for Gaussian (09 and 16), Orca (≥4.0), NWChem and (Open)Molcas. The toolkit can be used in command line, so that no programming experience is required, although it presents some features that can also be employed as a python application programming interface. We apply the toolkit in four situations in which different electronic-structure properties of organic molecules in the presence of a solvent or a complex biological environment are computed: the reduction potential of the nucleobases in acetonitrile, an energy decomposition analysis of tyrosine interacting with water, the absorption spectrum of an azobenzene derivative integrated into a voltage-gated ion channel, and the absorption and emission spectra of the luciferine/luciferase complex. These examples show that the toolkit can be employed in a manifold of situations for both the electronic ground state and electronically excited states. It also allows for the automatic correction of the active space in the case of CASSCF calculations on an ensemble of geometries, as it is shown for the azobenzene derivative photoswitch case.

We report major algorithmic improvements of the UNRES package for physics-based coarse-grained simulations of proteins. These include (i) introduction of interaction lists to optimize computations, (ii) transforming the inertia matrix to a pentadiagonal form to reduce computing and memory requirements, (iii) removing explicit angles and dihedral angles from energy expressions and recoding the most time-consuming energy/force terms to minimize the number of operations and to improve numerical stability, (iv) using OpenMP to parallelize those sections of the code for which distributed-memory parallelization involves unfavorable computing/communication time ratio, and (v) careful memory management to minimize simultaneous access of distant memory sections. The new code enables us to run molecular dynamics simulations of protein systems with size exceeding 100,000 amino-acid residues, reaching over 1 ns/day (1 μs/day in all-atom timescale) with 24 cores for proteins of this size. Parallel performance of the code and comparison of its performance with that of AMBER, GROMACS and MARTINI 3 is presented.

We introduce FCclasses3, a code to carry out vibronic simulations of electronic spectra and nonradiative rates, based on the harmonic approximation. Key new features are: implementation of the full family of vertical and adiabatic harmonic models, vibrational analysis in curvilinear coordinates, extension to several electronic spectroscopies and implementation of time-dependent approaches. The use of curvilinear valence internal coordinates allows the adoption of quadratic model potential energy surfaces (PES) of the initial and final states expanded at arbitrary configurations. Moreover, the implementation of suitable projectors provides a robust framework for defining reduced-dimensionality models by sorting flexible coordinates out of the harmonic subset, so that they can then be treated at anharmonic level, or with mixed quantum classical approaches. A set of tools to facilitate input preparation and output analysis is also provided. We show the program at work in the simulation of different spectra (one and two-photon absorption, emission and resonance Raman) and internal conversion rate of a typical rigid molecule, anthracene. Then, we focus on absorption and emission spectra of a series of flexible polyphenyl molecules, highlighting the relevance of some of the newly implemented features. The code is freely available at http://www.iccom.cnr.it/en/fcclasses/.

In the replica-permutation method, an advanced version of the replica-exchange method, all combinations of replicas and parameters are considered for parameter permutation, and a list of all the combinations is prepared. Here, we report that the temperature transition probability depends on how the list is created, especially in replica permutation with solute tempering (RPST). We found that the transition probabilities decrease at large replica indices when the combinations are sequentially assigned to the state labels as in the originally proposed list. To solve this problem, we propose to modify the list by randomly assigning the combinations to the state labels. We performed molecular dynamics simulations of amyloid-β(16-22) peptides using RPST with the "randomly assigned" list (RPST-RA) and RPST with the "sequentially assigned" list (RPST-SA). The results show the decreases in the transition probabilities in RPST-SA are eliminated, and the sampling efficiency is improved in RPST-RA.

Distribution of solvent molecules near transition-metal complex is key information to comprehend the functionality, reactivity, and so forth. However, polarizable continuum solvent models still are the standard and conventional partner of molecular-orbital (MO) calculations in the solution system including transition-metal complex. In this study, we investigate the conformation, hydration, and ligand substitution reaction between NO2 - and H2 O in aqueous solution for [Ru(NO)(OH)(NO2 )4 ]2- (A), [Ru(NO)(OH)(NO2 )3 (ONO)]2- (B), and [Ru(NO)(OH)(NO2 )3 (H2 O)]- (C) using a combination method of MO theories and a state-of-the-art molecular solvation technique (NI-MC-MOZ-SCF). A dominant species is found in the complex B conformers and, as expected, different between the solvent models, which reveals that molecular solvation beyond continuum media treatment are required for a reliable description of solvation near transition-metal complex. In the stability constant evaluation of ligand substitution reaction, an assumption that considers the direct association between the dissociated NO2 - and complex C is useful to obtain a reliable stability constant.

Update of bioRxiv. 2022 Jan 25;:

Si69 and Si75, typical commodities of silane coupling agents, are often employed in tire recipes to work as the bridges connecting silica and polymers, with which rolling resistance and wet traction are enhanced without loss in abrasion resistance. In this article, the reactivities of Si69 and Si75 with silica and various rubbers were theoretically investigated by using density functional theory (DFT). When the agents were coupled with silica, not only the acid+water condition but also the pure acid condition was confirmed to readily trigger the condensation reactions. The corresponding Gibbs free energy barriers were related to the charge distributions of reaction regions. As the agents suffered from the homolysis of central SS bonds, the generated single-S-tailer radicals (RS·) showed significantly higher reactivities of both the radical addition and the α-H transfer reactions with rubbers, due to the stronger radical philicities of the terminal sulfur radicals with larger condensed local softnesses [s0 (S)]. When the agents underwent the heterolysis of central SS bonds, the terminal sulfur anions with smaller s- (S) indices, however, facilitated the nucleophilic addition reactions with rubbers. Several derivative indices based on the condensed local softnesses were also proposed here to shed light on the reactivities from the viewpoint of the relationship between energy barriers and electronic characteristics. The above findings pave the way for the design of new kinds of silane coupling agents using computer-aided techniques, and meanwhile, provide references for the practical application of Si69 and Si75 to the silica/rubbers systems.

Quantum-mechanical-based computational design of molecular catalysts requires accurate and fast electronic structure calculations to determine and predict properties of transition-metal complexes. For Zr-based molecular complexes related to polyethylene catalysis, previous evaluation of density functional theory (DFT) and wavefunction methods only examined oxides and halides or select reaction barrier heights. In this work, we evaluate the performance of DFT against experimental redox potentials and bond dissociation enthalpies (BDEs) for zirconocene complexes directly relevant to ethylene polymerization catalysis. We also examined the ability of DFT to compute the fourth atomic ionization potential of zirconium and the effect the basis set selection has on the ionization potential computed with CCSD(T). Generally, the atomic ionization potential and redox potentials are very well reproduced by DFT, but we discovered relatively large deviations of DFT-calculated BDEs compared to experiment. However, evaluation of BDEs with CCSD(T) suggests that experimental values should be revisited, and our CCSD(T) values should be taken as most accurate.

Here, we investigate the performance of "Accurate NeurAl networK engINe for Molecular Energies" (ANI), trained on small organic compounds, on bulk systems including non-covalent interactions and applicability to estimate solvation (hydration) free energies using the interaction between the ligand and explicit solvent (water) from single-step MD simulations. The method is adopted from ANI using the Atomic Simulation Environment (ASE) and predicts the non-covalent interaction energies at the accuracy of wb97x/6-31G(d) level by a simple linear scaling for the conformations sampled by molecular dynamics (MD) simulations of ligand-n(H2 O) systems. For the first time, we test ANI potentials' abilities to reproduce solvation free energies using linear interaction energy (LIE) formulism by modifying the original LIE equation. Our results on ~250 different complexes show that the method can be accurate and have a correlation of R2  = 0.88-0.89 (MAE <1.0 kcal/mol) to the experimental solvation free energies, outperforming current end-state methods. Moreover, it is competitive to other conventional free energy methods such as FEP and BAR with 15-20 × fold reduced computational cost.

The nucleation of sulfuric acid-water clusters is a significant contribution to the formation of aerosols as precursors of cloud condensation nuclei (CCN). Depending on the temperature, there is an interplay between the clustering of particles and their evaporation controlling the efficiency of cluster growth. For typical temperatures in the atmosphere, the evaporation of H2 SO4 H2 O clusters is more efficient than the clustering of the first, small clusters, and thus their growth is dampened at its early stages. Since the evaporation rates of small clusters containing an HSO4- ion are much smaller than for purely neutral sulfuric acid clusters, they can serve as a central body for the further attachment of H2 SO4 H2 O molecules. We here present an innovative Monte Carlo model to study the growth of aqueous sulfuric acid clusters around central ions. Unlike classical thermodynamic nucleation theory or kinetic models, this model allows to trace individual particles and thus to determine properties for each individual particle. As a benchmarking case, we have performed simulations at T = 300 K a relative humidity of 50% with dipole and ion concentrations of cdipole = 5  ×  108 - 109 cm-3 and cion = 0 - 107 cm-3 . We discuss the runtime of our simulations and present the velocity distribution of ionic clusters, the size distribution of the clusters as well as the formation rate of clusters with radii R ≥ 0.85 nm . Simulations give reasonable velocity and size distributions and there is a good agreement of the formation rates with previous results, including the relevance of ions for the initial growth of sulfuric acid-water clusters. Conclusively, we present a computational method which allows studying detailed particle properties during the growth of aerosols as a precursor of CCN.

The quantum theory of atoms-in-molecules (QTAIM) method is used to examine the OO bond in peroxides (RO-OR) and nitroxide dimers (R2 NO-ONR2 ), including Fremy's salt. The electron density (ρ), electron kinetic energy density [K(ρ)], and Laplacian of the electron density (∇2 ρ) at bond critical points characterize the nature of the OO bond. The data distinguish OO bonding of two kinds. Large values of ρ and positive ∇2 ρ and K(ρ) suggest that simple peroxides have charge-shift bonds. Nitroxide dimers, with smaller ρ, positive ∇2 ρ, and near-zero K(ρ), show a lack of shared electron density, suggesting there is no conventional OO bonding in these molecules. QTAIM analysis at the B3LYP/6-311+G(d,p) level of theory gives results in agreement with valence-bond theory and X-ray diffraction characterizations of peroxide OO bonds as charge-shift bonds. In contrast, CCSD/cc-pVDZ calculations fail to agree with previous results because of an insufficient, single-determinant treatment of the charge-shift bond.

Flexible loops are paramount to protein functions, with action modes ranging from localized dynamics contributing to the free energy of the system, to large amplitude conformational changes accounting for the repositioning whole secondary structure elements or protein domains. However, generating diverse and low energy loops remains a difficult problem. This work introduces a novel paradigm to sample loop conformations, in the spirit of the hit-and-run (HAR) Markov chain Monte Carlo technique. The algorithm uses a decomposition of the loop into tripeptides, and a novel characterization of necessary conditions for Tripeptide Loop Closure to admit solutions. Denoting m the number of tripeptides, the algorithm works in an angular space of dimension 12 m. In this space, the hyper-surfaces associated with the aforementioned necessary conditions are used to run a HAR-like sampling technique. On classical loop cases up to 15 amino acids, our parameter free method compares favorably to previous work, generating more diverse conformational ensembles. We also report experiments on a 30 amino acids long loop, a size not processed in any previous work.

The nudged elastic band (NEB) method is utilized to find reaction paths (RPs) using discretized intermediate structures called "images" between a reactant and a product. In fact, NEB calculations do not always converge because of the bent of RPs. Mathematically, more images are needed for complex curves, and here, we focused on the curvature. In this study, we propose a new method for calculating the curvature of the RPs as well as a method for weighting the spring constant of the NEB with the curvature, which we named the curvature weighted NEB (CW-NEB) method. In addition, we will propose the CW-NEB method with the climbing image (CI) method (CW-CI-NEB). To show the efficiency of our method, calculations for the ene-reaction of the CW-CI-NEB method were performed and compared with those of the CI-NEB methods. The CW-CI-NEB methods converged in shorter iteration times than the CI-NEB calculation, which was found by gathering the bent of RPs.

Fanpy is a free and open-source Python library for developing and testing multideterminant wavefunctions and related ab initio methods in electronic structure theory. The main use of Fanpy is to quickly prototype new methods by making it easier to convert the mathematical formulation of a new wavefunction ansätze to a working implementation. Fanpy is designed based on our recently introduced Flexible Ansatz for N-electron Configuration Interaction (FANCI) framework, where multideterminant wavefunctions are represented by their overlaps with Slater determinants of orthonormal spin-orbitals. In the simplest case, a new wavefunction ansatz can be implemented by simply writing a function for evaluating its overlap with an arbitrary Slater determinant. Fanpy is modular in both implementation and theory: the wavefunction model, the system's Hamiltonian, and the choice of objective function are all independent modules. This modular structure makes it easy for users to mix and match different methods and for developers to quickly explore new ideas. Fanpy is written purely in Python with standard dependencies, making it accessible for various operating systems. In addition, it adheres to principles of modern software development, including comprehensive documentation, extensive testing, quality assurance, and continuous integration and delivery protocols. This article is considered to be the official release notes for the Fanpy library.

The ability to accurately and rapidly evaluate the intermolecular many-body polarization effect of the water system is very important for computer simulations of biomolecule in aqueous. In this paper, a scheme is proposed based on the polarizable dipole-dipole interaction model and used to rapidly estimate the intermolecular many-body polarization effect in water clusters. We use a bond-dipole-based polarization function to evaluate the polarization energy. We regard two OH bonds of a water molecule as two bond-dipoles and set the permanent OH bond-dipole moment of a water molecule to be 1.51 Debye. We estimate the induced OH bond-dipole moment via a simple formula in which only one correction factor is needed. This scheme is then applied to tens of water clusters to calculate the three- and four-body interaction energies. The three-body interaction energies of 93 water clusters produced by our scheme are compared with those produced by the counterpoise-corrected CCSD(T)/aug-cc-pVDZ, MP2/aug-cc-pVDZ, M06-2X/jul-cc-pVTZ methods, by the AMOEBApro13, iAMOEBA, AMOEBA+, AMOEBA+(CF) methods, and by the MB-pol method. The four-body interaction energies of 47 water clusters yielded by our scheme are compared with those yielded by the counterpoise-corrected MP2/aug-cc-pVDZ and M06-2X/ jul-cc-pVTZ methods, by the AMOEBApro13, AMOEBA+, AMOEBA+(CF) methods, and by the MB-pol method. The comparison results show that the scheme proposed in this paper can reproduce the counterpoise-corrected CCSD(T)/aug-cc-pVDZ three-body interaction energies and reproduce the counterpoise-corrected MP2/aug-cc-pVDZ four-body interaction energies both accurately and efficiently. We anticipate the scheme proposed here can be useful for computer simulations of liquid water and aqueous solutions.

Oxindoles are an important class of heterocyclic alkaloids with demonstrated pharmacological activity at multiple biological targets. Preparation of new analogs through novel synthetic routes is therefore highly attractive. In this work, we report a computational study to investigate the synthesis of ethoxycarbonyldifluoromethylated oxindoles from N-arylmethacrylamides. The reaction tolerates a diverse range of acrylamides, shows yields ranging from approximately 38%-96%. We have applied density functional theory (DFT) to explore the reaction mechanism, kinetics and thermodynamics to gain further understanding. We demonstrate that a radical-based ring closure reaction is energetically more favorable than a heterolytic process, that the rate-determining step is the formation of the arylmethacrylamide radical, and that the product yields and selectivities are consistent with experiment. The results demonstrate that theoretical methods can prove useful to understand how such reaction and could be potentially employed to rapidly explore the reaction scope further.

In this work, we present a fully automated method for the construction of chemically meaningful sets of hierarchical nonredundant internal coordinates (ICs; also commonly denoted as Z-matrices) from the Cartesian coordinates of a molecular system. Particular focus is placed on avoiding ill-definitions of angles and dihedrals due to linear arrangements of atoms, to consistently guarantee a well-defined transformation to Cartesian coordinates, even after structural changes. The representations thus obtained are particularly well suited for pathway construction in double-ended methods for transition state search and optimizations with nonlinear constraints. Analytical gradients for the transformation between the coordinate systems were derived for analytical geometry optimizations purely in Z-matrix coordinates. The geometry optimization was coupled with a Symbolic Algebra package to support arbitrary nonlinear constraints in Z-matrix coordinates, while retaining analytical energy gradient conversion. The difference to the commonly used nonhierarchical IC transformations is discussed. Sample applications are provided for a number of common chemical reactions and illustrative examples.

The impact of complete basis set extrapolation schemes (CBS), diffuse functions, and tight weighted-core functions on enthalpies of formation predicted via the DLPNO-CCSD(T1) reduced Feller-Peterson-Dixon approach has been examined for neutral H,C,O-compounds. All tested three-point (TZ/QZ/5Z) extrapolation schemes result in mean unsigned deviation (MUD) below 2 kJ mol-1 relative to the experiment. The two-point QZ/5Z and TZ/QZ CBS 1/lmax3 extrapolation schemes are inferior to their inverse power counterpart ( 1/(lmax+1/2)4 ) by 1.3 and 4.3 kJ mol-1 . The CBS extrapolated frozen core atomization energies are insensitive (within 1 kJ mol-1 ) to augmentation of the basis set with tight weighted core functions. The core-valence correlation effects converge already at triple-ζ, although double-ζ/triple-ζ CBS extrapolation performs better and is recommended. The effect of diffuse function augmentation converges slowly, and cannot be reproduced with double- ζ or triple- ζ calculations as these are plagued with basis set superposition and incompleteness errors.

The proper and precise reproduction of the molecular electrostatic potential (MEP) is crucial to describe correctly electrostatic interactions in molecular modeling. Most of the classical molecular mechanics force fields for biomolecules and drug-like molecules use the atom-centered point charges to describe MEP. However, it has been systematically pointed out in literature that such an approximation is not always enough, and some groups, like amino group or heavy halogens, require the use of anisotropic model for better description of their MEP. At the same time, the formally charged groups have not been as extensively and systematically studied as their neutral counterparts. In this report, we demonstrate that the anisotropic models for formally charged groups do bring improvements in the reference MEP reproduction, that are comparable in magnitude to those for neutral groups.