Flavins are employed as redox cofactors and chromophores in a plethora of flavoenzymes. Their versatility is an outcome of intrinsic molecular properties of the isoalloxazine ring modulated by the protein scaffold and surrounding solvent. Thus, an investigation of isolated flavins with high-level electronic-structure methods and with error assessment of the calculated properties will contribute to building better models of flavin reactivity. Here, we benchmarked ground-state properties such as electron affinity, gas-phase basicity, dipole moment, torsion energy, and tautomer stability for lumiflavins in all biologically relevant oxidation and charge states. Overall, multiconfigurational effects are small and chemical accuracy is achieved by coupled-cluster treatments of energetic properties. Augmented basis sets and extrapolations to the complete basis-set limit are necessary for consistent agreement with experimental energetics. Among DFT functionals tested, M06-2X shows the best performance for most properties, except gas-phase basicity, in which M06 and CAM-B3LYP perform better. Moreover, dipole moments of radical flavins show large deviations for all functionals studied. Tautomers with noncanonical protonation states are significantly populated at normal temperatures, adding to the complexity of modeling flavins. These results will guide future computational studies of flavoproteins and flavin chemistry by indicating the limitations of electronic-structure methodologies and the contributions of multiple tautomeric states.

A next-generation protocol (Poltype 2) has been developed which automatically generates AMOEBA polarizable force field parameters for small molecules. Both features and computational efficiency have been drastically improved. Notable advances include improved database transferability using SMILES, robust torsion fitting, non-aromatic ring torsion parameterization, coupled torsion-torsion parameterization, Van der Waals parameter refinement using ab initio dimer data and an intelligent fragmentation scheme that produces parameters with dramatically reduced ab initio computational cost. Additional improvements include better local frame assignment for atomic multipoles, automated formal charge assignment, Zwitterion detection, smart memory resource defaults, parallelized fragment job submission, incorporation of Psi4 quantum package, ab initio error handling, ionization state enumeration, hydration free energy prediction and binding free energy prediction. For validation, we have applied Poltype 2 to ~1000 FDA approved drug molecules from DrugBank. The ab initio molecular dipole moments and electrostatic potential values were compared with Poltype 2 derived AMOEBA counterparts. Parameters were further substantiated by calculating hydration free energy (HFE) on 40 small organic molecules and were compared with experimental data, resulting in an RMSE error of 0.59 kcal/mol. The torsion database has expanded to include 3543 fragments derived from FDA approved drugs. Poltype 2 provides a convenient utility for applications including binding free energy prediction for computational drug discovery. Further improvement will focus on automated parameter refinement by experimental liquid properties, expansion of the Van der Waals parameter database and automated parametrization of modified bio-fragments such as amino and nucleic acids.

Both the experimental and calculated data reveal that a strong NH⋯OС intramolecular hydrogen bond closing the seven-membered quasi-cycle is formed in the Z-isomers of pyrrolylenones. Comparison of the NH⋯OС intramolecular hydrogen bonds energies in the pyrrolylenones, estimated via the molecular tailoring approach, with the similar data for reference malonaldehydes shows that the resonance-assisted hydrogen bonding occurs in both cases, the hydrogen bond energy being varied mainly within 10-20 kcal/mol. The combined application of function-based and molecular tailoring approaches makes it possible to decompose the NH⋯OС total hydrogen bond energy in the pyrrolylenones into the π- and σ-components. It is established that the contribution of the π-component to the total N(O)H⋯OС hydrogen bond energy in the pyrrolylenones and malonaldehydes is almost the same (6-7 kcal/mol). Comparison of the π-contribution to the total energy of the resonance-assisted hydrogen bonding in the Z-isomer of pyrrolylenones with the energy of the push-pull effect in the E-isomer of pyrrolylenones reveals that the resonance contribution to the total energy of the resonance-assisted hydrogen bond in the former significantly enhances with reference to the net resonance energy in the latter. The appearance of the resonance-assisted hydrogen bond in the pyrrolylenones is possible due to the participation in the interaction of 10 or 14 π-electrons satisfying the Hückel aromaticity rule.

Chagas disease is caused by Trypanosoma cruzi. Benznidazole and nifurtimox are drugs used for its therapy; nevertheless, they have collateral effects. NADH-fumarate (FUM) reductase is a potential pharmacological target since it is essential for survival of parasite and is not found in humans. The objectives are to design and characterize the electronic structure of imidazole and nitroimidazole derivatives at DFT-M06-2X level in aqueous solution; also, to model the NADH-FUM reductase and analyze its intermolecular interactions by molecular docking. Quantum-chemical descriptors allowed to select the molecules with the best physicochemical properties and lowest toxicity. A high-quality three-dimensional structure of NADH-FUM reductase was obtained by homology modeling. Water molecules do not have influence in the interaction between FUM and NADH-FUM reductase. The main hydrogen-binding interactions for FUM were identified in NADH, Lys172, and Arg89; while hydrophobic interactions in Phe479, Thr174, Met63. The molecules S3-8, S2-8, and S1-8 could be inhibitors of NADH-FUM reductase.

Arenes [C6 H3 R(TMS)(OTf); also called benzyne/aryne precursors] containing inter-related leaving groups Me3 Si (TMS) and CF3 SO3 (OTf) on the adjacent positions (1,2-position) are generally converted to their corresponding aryne-intermediates via the addition of fluoride anion (F- ) and subsequent elimination of TMS and OTf groups. This reaction is believed to proceed via the formation of an anionic intermediate [C6 H4 (TMS-F)(OTf)]- . The EDA-NOCV analysis (EDA-NOCV = energy decomposition analysis-natural orbital for chemical valence) of over 35 such precursors of varied types have been reported to reveal bonding and stability of CAr Si and COTf bonds. EDA-NOCV showed that the nature of the CAr Si bond of C6 H3 R(TMS)(OTf) can be expressed as both dative and electron sharing [CAr Si, CAr →Si]. The CAr OTf bond, on the other hand, can be described explicitly as dative [CAr ←OTf]. The nature of CAr Si bond of [C6 H4 (TMS-F)(OTf)]- exclusively changes to covalent dative σ-bond CAr →S(Me)3F on the attachment of F- to the TMS group of C6 H4 (TMS)(OTf). Introduction of σ-electron withdrawing group (like OMe, NMe2 , and NO2 ) to the ortho-position of the TMS group of functionalized arynes C6 H3 R(TMS)(OTf) prefer to have a covalent dative σ-bond (CAr →Si) over an electron-sharing covalent σ-bond (CAr Si). If this σ-electron withdrawing group is shifted from ortho-position to meta- and para-positions, then the preference for a dative bond decreases significantly, implying that the electronic effect on the nature of chemical bonds affects through bond paths. This effect dies with distance, similar to the well-known inductive effect.

This article presents SlaterGPU, a graphics processing unit (GPU) accelerated library that uses OpenACC to numerically compute Slater-type orbital (STO) integrals. The electron repulsion integrals (ERI) are computed under the RI approximation using the Coulomb potential of the Slater basis function. To fully realize the performance capabilities of modern GPUs, the Slater integrals are evaluated in mixed-precision, resulting in speedups for the ERIs of over 80×. Parallelization on multiple GPUs allows for integral throughput of over 3 million integrals per second. This places STO integral throughput within reach of single-threaded, conventional Gaussian integration schemes. To test the quality of the integrals, the fluorine exchange reaction barrier in fluoromethane was computed using heat-bath configuration interaction (HBCI). In addition, the singlet-triplet gap of cyclobutadiene was examined using HBCI in a triple- ζ , polarized basis set. These benchmarks demonstrate the library's ability to generate the full set of integrals necessary for configuration interaction with up to 6h functions in the auxiliary basis.

This paper describes ppdx, a python workflow tool that combines protein sequence alignment, homology modeling, and structural refinement, to compute a broad array of descriptors for characterizing protein-protein interactions. The descriptors can be used to predict various properties of interest, such as protein-protein binding affinities, or inhibitory concentrations (IC50 ), using approaches that range from simple regression to more complex machine learning models. The software is highly modular. It supports different protocols for generating structures, and 95 descriptors can be currently computed. More protocols and descriptors can be easily added. The implementation is highly parallel and can fully exploit the available cores in a single workstation, or multiple nodes on a supercomputer, allowing many systems to be analyzed simultaneously. As an illustrative application, ppdx is used to parametrize a model that predicts the IC50 of a set of antigens and a class of antibodies directed to the influenza hemagglutinin stalk.

Explicitly correlated calculations, aside from the orbital basis set, typically require three auxiliary basis sets: Coulomb-exchange fitting (JK), resolution of the identity MP2 (RI-MP2), and complementary auxiliary basis set (CABS). If unavailable for the orbital basis set and chemical elements of interest, the first two can be auto-generated on the fly using existing algorithms, but not the third. In this paper, we present a quite simple algorithm named autoCABS; a Python implementation under a free software license is offered at Github. For the cc-pVnZ-F12 (n = D,T,Q,5), the W4-08 thermochemical benchmark, and the HFREQ2014 set of harmonic frequencies, we demonstrate that autoCABS-generated CABS basis sets are comparable in quality to purpose-optimized OptRI basis sets from the literature, and that the quality difference becomes entirely negligible as n increases.

Aldimine derivatives chromophores grafted on polyacetylene oligomers were first designed to investigate the nonlinear optical (NLO) response of the resulting materials using CAMB3LYP method. The effects of different factors such as the chain length separating the substitutions as well as the configurations and the orientations of these latter, were examined and discussed. In a second part of this paper, NLO responses, in particular the static hyperpolarizabilities of polyvinyl oligomers substituted by aldimine chromophores via carboxylic groups and by pyrrolidone groups were calculated for different configurations. The stability and the hydrogen bonding in each oligomer were also discussed.

The ion association is widely believed to be dominated by the favorable entropy change arising from the release of water molecules from ion hydration shells. However, no direct thermodynamic evidence exists to validate the reliability and suitability of this view. Herein, we employ complicated free energy calculations to rigorously split the free energy including its entropic and enthalpic components into the water-induced contributions and ion-ion interaction terms for several ion pairs from monatomic to polyatomic ions, spanning the size range from small kosmotropes to large chaotropes (Na+ , Cs+ , Ca2+ , F- , I- , CO3 2- , and HPO4 2- ). Our results successfully reveal that though ion associations are indeed determined by a delicate balance between the favorable entropy variation and the repulsive enthalpy change, the entropy gain dominated by the solvent occurs only for the monatomic ion pairing. The water-induced entropic contribution significantly goes against the ion pairing between polyatomic anion and cation, which is, alternatively, dominated by the favorable entropy from the ion-ion interaction term, due to the configurational arrangement of polyatomic anions involved in ion association. The structural and dynamic analysis demonstrates that the entropy penalty from the water phase is primarily ascribed to the enhanced stability of water molecules around the cation imposed by the incoming anion. Our study successfully provides a fundamental understanding of water-mediated ion associations and highlights disparate lengthscale dependencies of the dehydration thermodynamics on the specific types of ions.

The exploration of a reaction network requires highly automated workflows to avoid error-prone and time-consuming manual steps. In this respect, a major bottleneck is the search for transition-state (TS) structures, which frequently fails and, therefore, makes (manual) revision necessary. In this work, we present a technique for obtaining suitable input structures for automated TS searches based on single-ended reaction path optimization algorithms, which makes subsequent TS searches via this method significantly more robust. First, possible input structures are generated based on the spatial alignment of the reactants. The appropriate orientation of reacting groups is achieved via stepwise rotations along selected torsional degrees of freedom. Second, a ranking of the obtained structures is performed according to selected geometric criteria. The main goals are to properly align the reactive atoms, to avoid hindrance within the reaction channel and to resolve steric clashes between the reactants. The developed procedure has been carefully tested on a variety of examples and provides suitable input structures for TS searches within seconds. The method is in daily use in an industrial setting.

We present a series of new implementations that we recently introduced in COBRAMM, the open-source academic software developed in our group. The goal of these implementations is to offer an automatized workflow and interface to simulate time-resolved transient absorption (TA) spectra of medium-to-big chromophore embedded in a complex environment. Therefore, the excited states absorption and the stimulated emission are simulated along nonadiabatic dynamics performed with trajectory surface hopping. The possibility of treating systems from medium to big size is given by the use of time-dependent density functional theory (TD-DFT) and the presence of the environment is taken into account employing a hybrid quantum mechanics/molecular mechanics (QM/MM) scheme. The full implementation includes a series of auxiliary scripts to properly setup the QM/MM system, the calculation of the wavefunction overlap along the dynamics for the propagation, the evaluation of the transition dipole moment at linear response TD-DFT level, and scripts to setup, run and analyze the TA from an ensemble of trajectories. Altogether, we believe that our implementation will open the door to the easily simulate the time-resolved TA of systems so far computationally inaccessible.

Per- and polyfluoroalkyl substances (PFAS) have been widely used the past 70 years in numerous applications due to their chemical and thermal stability. Due to their robust stability, they are environmentally recalcitrant which made them one of the most persistent environmental contaminants. In addition to strong CF bond strength, oleophobicity, hydrophobicity, and high reduction-oxidation (redox) potential of PFAS has led to their inefficient degradation by traditional means. A characteristic of their structure is also their preference to adopt helical conformations along the carbon backbone, contrary to their hydrocarbon analogues. This work investigates the helical nature of perfluoroalkanes through their conformational distributions, especially as a benchmark for determining the impact of polar head groups, heteroatoms, and radical center on helical conformations. Since structure governs reactivity and molecular properties, it is important to assess if minor chemical perturbations in the structure will lead to changes in the conformations. Based on density functional theory calculations and comprehensive conformational distributions, it was concluded that the helicity is a local structural property which changes significantly with the presence of heteroatoms in the perfluoroalkyl chain as well as with the presence of radical centers.

In this report, we study the ordering of C60 , Sc3 N@C80 , and Dy2 ScN@C80 molecules on different metallic and dielectric surfaces such as Ag(100), Au(111), and MgO(100). By using DFT techniques, we can classify different types of cage-to-surface arrangements and their relative energies. Using a proposed homogenous sampling of the conformational space for the M3 N cluster, we determine a potential energy map that is capable of providing a structural distribution for a given energy window. We find that Coulomb interaction is a dominant force that governs the system's stability and order. However, a deep analysis of the charge density rearrangements reveals that even though the integral charges may be considered as a qualitative control parameter, it fails to provide quantitative data due to the importance of spatial characteristics of charge densities.

Glycosaminoglcyans (GAGs), linear anionic periodic polysaccharides, are crucial for many biologically relevant functions in the extracellular matrix. By interacting with proteins GAGs mediate processes such as cancer development, cell proliferation and the onset of neurodegenerative diseases. Despite this eminent importance of GAGs, they still represent a limited focus for the computational community in comparison to other classes of biomolecules. Therefore, there is a lack of modeling tools designed specifically for docking GAGs. One has to rely on existing docking software developed mostly for small drug molecules substantially differing from GAGs in their basic physico-chemical properties. In this study, we present an updated protocol for docking GAGs based on the Repulsive Scaling Replica Exchange Molecular Dynamics (RS-REMD) that includes explicit solvent description. The use of this water model improved docking performance both in terms of its accuracy and speed. This method represents a significant computational progress in GAG-related research.