Anharmonic Vibrational Spectroscopy of Germanium-Containing Clusters, GexC4-x and GexSi4-x (x = 0-4), for Interstellar Detection.

An extensive, high-level theoretical study on tetra-atomic germanium carbide/silicide clusters is presented. Accurate harmonic and anharmonic vibrational frequencies and rotational constants are calculated at the CCSD(T)-F12a(b)/cc-pVT(Q)Z-F12 levels of theory. With growing capabilities to discern more of the chemical composition of the interstellar medium (ISM), an accurate database of reference material is required. The presence of carbon is ubiquitous in the ISM, and silicon is known to be present in interstellar dust grains; however, germanium-containing molecules remain elusive. To begin understanding the presence and role of germanium in the ISM, we present this study of the vibrational and rotational spectroscopic properties of various germanium-containing molecules to aid in their potential identification in the ISM with modern observational tools such as the James Webb Space Telescope. Structures studied herein include rhomboidal (r-), diamond (d-), and trapezoidal (t-) tetra-atomic molecules of the form GexC4-x and GexSi4-x, where x = 0-4. The most promising structure for detection is r-Ge2C2 via the ν4 mode with a frequency of 802.7 cm-1 (12.5 µm) and an intensity of 307.2 km mol-1. Other molecules that are potentially detectable, i.e., through vibrational modes or rotational transitions, include r-Ge3C, r-GeSi3, d-GeC3, r-GeC3, and t-Ge2C2.

The Effects of Ring Strain on Cyclic Tetraaryl[5]cumulenes.

Cyclic tetraaryl[5]cumulenes (1 a-f) have been synthesized and studied as a function of increasing ring strain. The magnitude of ring strain is approximated by the extent of bending of the cumulenic core as assessed by a combination of X-ray crystallographic analysis and DFT calculations. Trends are observed in 13 C NMR, UV-vis, and Raman spectra associated with ring strain, but the effects are small. In particular, the experimental HOMO-LUMO gap is not appreciably affected by bending of the [5]cumulene framework from ca. 174° (λmax =504 nm) in 1 a to ca. 178° (λmax =494 nm) in 1 f.

Computational Prediction and Experimental Validation of the Unique Molecular Mode of Action of Scoulerine.

Scoulerine is a natural compound that is known to bind to tubulin and has anti-mitotic properties demonstrated in various cancer cells. Its molecular mode of action has not been precisely known. In this work, we perform computational prediction and experimental validation of the mode of action of scoulerine. Based on the existing data in the Protein Data Bank (PDB) and using homology modeling, we create human tubulin structures corresponding to both free tubulin dimers and tubulin in a microtubule. We then perform docking of the optimized structure of scoulerine and find the highest affinity binding sites located in both the free tubulin and in a microtubule. We conclude that binding in the vicinity of the colchicine binding site and near the laulimalide binding site are the most likely locations for scoulerine interacting with tubulin. Thermophoresis assays using scoulerine and tubulin in both free and polymerized form confirm these computational predictions. We conclude that scoulerine exhibits a unique property of a dual mode of action with both microtubule stabilization and tubulin polymerization inhibition, both of which have similar affinity values.

Multireference Methods for Calculating the Dissociation Enthalpy of Tetrahedral P4 to Two P2.

The potential energy surface for the thermal decomposition of P4 → 2P2 was computed along the C2 v reaction trajectory. Single-reference methods were not suitable for describing this complex bond-breaking process, so two multiconfigurational methods, namely, multistate complete active space second-order perturbation theory (MS-CASPT2) and multiconfiguration pair-density functional theory (MC-PDFT), were used with the aim of determining the accuracy and efficiency of these methods for this process. Several active spaces and basis sets were explored. It was found that the multiconfiguration pair-density functional theory method was up to 900 times faster than multistate complete active space second-order perturbation theory while providing similar accuracy.

Explaining the Microtubule Energy Balance: Contributions Due to Dipole Moments, Charges, van der Waals and Solvation Energy.

Microtubules are the main components of mitotic spindles, and are the pillars of the cellular cytoskeleton. They perform most of their cellular functions by virtue of their unique dynamic instability processes which alternate between polymerization and depolymerization phases. This in turn is driven by a precise balance between attraction and repulsion forces between the constituents of microtubules (MTs)-tubulin dimers. Therefore, it is critically important to know what contributions result in a balance of the interaction energy among tubulin dimers that make up microtubules and what interactions may tip this balance toward or away from a stable polymerized state of tubulin. In this paper, we calculate the dipole-dipole interaction energy between tubulin dimers in a microtubule as part of the various contributions to the energy balance. We also compare the remaining contributions to the interaction energies between tubulin dimers and establish a balance between stabilizing and destabilizing components, including the van der Waals, electrostatic, and solvent-accessible surface area energies. The energy balance shows that the GTP-capped tip of the seam at the plus end of microtubules is stabilized only by - 9 kcal/mol, which can be completely reversed by the hydrolysis of a single GTP molecule, which releases + 14 kcal/mol and destabilizes the seam by an excess of + 5 kcal/mol. This triggers the breakdown of microtubules and initiates a disassembly phase which is aptly called a catastrophe.

Detailed Per-residue Energetic Analysis Explains the Driving Force for Microtubule Disassembly.

Microtubules are long filamentous hollow cylinders whose surfaces form lattice structures of αß-tubulin heterodimers. They perform multiple physiological roles in eukaryotic cells and are targets for therapeutic interventions. In our study, we carried out all-atom molecular dynamics simulations for arbitrarily long microtubules that have either GDP or GTP molecules in the E-site of ß-tubulin. A detailed energy balance of the MM/GBSA inter-dimer interaction energy per residue contributing to the overall lateral and longitudinal structural stability was performed. The obtained results identified the key residues and tubulin domains according to their energetic contributions. They also identified the molecular forces that drive microtubule disassembly. At the tip of the plus end of the microtubule, the uneven distribution of longitudinal interaction energies within a protofilament generates a torque that bends tubulin outwardly with respect to the cylinder's axis causing disassembly. In the presence of GTP, this torque is opposed by lateral interactions that prevent outward curling, thus stabilizing the whole microtubule. Once GTP hydrolysis reaches the tip of the microtubule (lateral cap), lateral interactions become much weaker, allowing tubulin dimers to bend outwards, causing disassembly. The role of magnesium in the process of outward curling has also been demonstrated. This study also showed that the microtubule seam is the most energetically labile inter-dimer interface and could serve as a trigger point for disassembly. Based on a detailed balance of the energetic contributions per amino acid residue in the microtubule, numerous other analyses could be performed to give additional insights into the properties of microtubule dynamic instability.

Inactivation of Protein Tyrosine Phosphatases by Peracids Correlates with the Hydrocarbon Chain Length.

BACKGROUND/AIMS: Protein tyrosine phosphatases are crucial enzymes controlling numerous physiological and pathophysiological events and can be regulated by oxidation of the catalytic domain cysteine residue. Peracids are highly oxidizing compounds, and thus may induce inactivation of PTPs. The aim of the present study was to evaluate the inhibitory effect of peracids with different length of hydrocarbon chain on the activity of selected PTPs. METHODS: The enzymatic activity of human CD45, PTP1B, LAR, bacterial YopH was assayed under the cell-free conditions, and activity of cellular CD45 in human Jurkat cell lysates. The molecular docking and molecular dynamics were performed to evaluate the peracids binding to the CD45 active site. RESULTS: Here we demonstrate that peracids reduce enzymatic activity of recombinant CD45, PTP1B, LAR, YopH and cellular CD45. Our studies indicate that peracids are more potent inhibitors of CD45 than hydrogen peroxide (with an IC50 value equal to 25 nM for peroctanoic acid and 8 µM for hydrogen peroxide). The experimental data show that the inactivation caused by peracids is dependent on hydrocarbon chain length of peracids with maximum inhibitory effect of medium-chain peracids (C8-C12 acyl chain), which correlates with calculated binding affinities to the CD45 active site. CONCLUSION: Peracids are potent inhibitors of PTPs with the strongest inhibitory effect observed for medium-chain peracids.

Analysis of the strength of interfacial hydrogen bonds between tubulin dimers using quantum theory of atoms in molecules.

Microtubules are key structural elements that, among numerous biological functions, maintain the cytoskeleton of the cell and have a major role in cell division, which makes them important cancer chemotherapy targets. Understanding the energy balance that brings tubulin dimers, the building blocks of microtubules, together to form a microtubule is especially important for revealing the mechanism of their dynamic instability. Several studies have been conducted to estimate various contributions to the free energy of microtubule formation. However, the hydrogen-bond contribution was not studied before as a separate component. In this work, we use concepts such as the quantum theory of atoms in molecules to estimate the per-residue strength of hydrogen bonds contributing to the overall stability that brings subunits together in pair of tubulin heterodimers, across both the longitudinal and lateral interfaces. Our study shows that hydrogen bonding plays a major role in the stability of tubulin systems. Several residues that are crucial to the binding of vinca alkaloids are shown to be strongly involved in longitudinal microtubule stabilization. This indicates a direct relation between the binding of these agents and the effect on the interfacial hydrogen-bonding network, and explains the mechanism of their action. Lateral contacts showed much higher stability than longitudinal ones (-462 ± 70 vs. -392 ± 59 kJ/mol), which suggests a dramatic lateral stabilization effect of the GTP cap in the ß-subunit. The role of the M-loop in lateral stability in absence of taxol was shown to be minor. The B-lattice lateral hydrogen bonds are shown to be comparable in strength to the A-lattice ones (-462 ± 70 vs. -472 ± 46 kJ/mol). These findings establish the importance of hydrogen bonds to the stability of tubulin systems.

Mathematical and computational modeling in biology at multiple scales.

A variety of topics are reviewed in the area of mathematical and computational modeling in biology, covering the range of scales from populations of organisms to electrons in atoms. The use of maximum entropy as an inference tool in the fields of biology and drug discovery is discussed. Mathematical and computational methods and models in the areas of epidemiology, cell physiology and cancer are surveyed. The technique of molecular dynamics is covered, with special attention to force fields for protein simulations and methods for the calculation of solvation free energies. The utility of quantum mechanical methods in biophysical and biochemical modeling is explored. The field of computational enzymology is examined.

Calibration and applications of the ΔMP2 method for calculating core electron binding energies.

We calibrated a method for the evaluation of core electron binding energies, based on the energy differences between the cation and neutral molecule evaluated at the level of Møller-Plesset perturbation theory. The central feature of the method is the use of a mixed basis set: a large all-electron basis set is used for the atom whose core electron is removed, while the model core potential basis set is employed for all remaining atoms. Calibration was carried out for 55 molecules and 114 binding energies of 1s core electrons for the atoms C, N, O, and F. The average absolute deviation for all the core electron binding energies is 0.163 eV. The method was applied to the calculation of the core electron binding energies of five nucleic acid bases (uracil, adenine, cytosine, guanine, and thymine) and several of their low-energy tautomers.

Performance of dynamically weighted multiconfiguration self-consistent field and spin-orbit coupling calculations of diatomic molecules of Group 14 elements.

The efficacy of several multiconfiguration self-consistent field (MCSCF) methods in the subsequent spin-orbit coupling calculations was studied. Three MCSCF schemes to generate molecular orbitals were analyzed: state-specific, state-averaged, and dynamically weighted MCSCF. With Sn(2)(+) as the representative case, we show that the state-specific MCSCF orbitals lead to discontinuities in potential energy curves when avoided crossings of electronic states occur; this problem can be solved using the state-averaged or dynamically weighted MCSCF orbitals. The latter two schemes are found to give similar results when dynamic electron correlation is considered, which we calculated at the level of multiconfigurational quasidegenerate perturbation theory (MCQDPT). We employed the recently developed Douglas-Kroll spin-orbit adapted model core potential, ZFK3-DK3, and the dynamically weighted MCSCF scheme to calculate the spectroscopic constants of the mono-hydrides and compared them to the results obtained using the older set of potentials, MCP-TZP. We also showed that the MCQDPT tends to underestimate the dissociation energies of the hydrides and discussed to what extent coupled-cluster theory can be used to improve results.

Two-component natural spinors from two-step spin-orbit coupled wave functions.

We developed an algorithm to obtain the natural orbitals (natural spinors) from the two-step spin-orbit coupled wave functions. These natural spinors are generally complex-valued, mixing two spin components, and they can have similar symmetry properties as the j-j spinors from the one-step spin-orbit coupling calculations, if the reduced density equally averages all the components of a multi-dimensional irreducible representation. Therefore, the natural spinors can serve as an approximation to the j-j spinors and any wave function analysis based on the j-j spinors can also be performed based on them. The comparison between the natural spinors and the j-j spinors of three representative atoms, Tl, At, and Lu, shows their close similarity and demonstrates the ability of the natural spinors to approximate the j-j spinors.

Model core potential and all-electron studies of molecules containing rare gas atoms.

Molecules HRgF (Rg = Ar, Kr, Xe, Rn) were studied at levels of theory that included electron correlation, taking relativistic effects into account either by using the recently developed parametrization of the extended model core potentials and basis sets or by using the Douglas-Kroll method with all-electron basis sets. Charge distributions were calculated according to Mulliken, Lowdin, and natural bond orbital methods of population analysis and the results of these methods were compared, confirming that bonding in these molecules corresponds to interaction between the fluoride anion and the RgH(+) moiety. In contrast to previously reported results, the present calculations show that the radon compound, HRnF, is more stable than compounds of the lighter congeners. Trends in the first ionization energies, bond lengths, energies of formation and decomposition, and harmonic vibrational frequencies were discussed and found to be consistent with the periodic trends of the atomic properties of the rare gas atoms.

Model core potentials of p-block elements generated considering the Douglas-Kroll relativistic effects, suitable for accurate spin-orbit coupling calculations.

Model core potentials with scalar-relativistic effect at the third order Douglas-Kroll level combined with the first-order Douglas-Kroll for spin-orbit coupling are developed for the 25 p-block elements, B-Tl, with the valence space starting at (n-1)p(n-1)d, except group 13, where (n-1)s is also included because its importance was clearly demonstrated for Tl. All of the comparisons between model core potential and all-electron calculations of atomic and ionic term and level energies and the spectroscopic constants of monohydrides and cationic dimers indicate the chemical accuracy of our new potentials in reproducing all-electron properties. The applications of the new potentials to the cationic dimers show that polyatomic calculations with model core potential atoms are accurate. The periodic trends in the spectroscopic properties of cationic dimers and hydrides are discussed. The timing study demonstrates the extent of the computational savings. These new sets of model core potentials and basis sets, which we call ZFKn-DK3, have been implemented in the the widely used quantum chemistry program package GAMESS-U.S.

Multireference study of spin-orbit coupling in the hydrides of the 6p-block elements using the model core potential method.

Careful spin-orbit multireference studies were carried out for the late p-block elements Tl, Pb, Bi, Po, At, and Rn and their hydrides using the model core potentials developed in the present work. The model core potentials were designed to treat the scalar-relativistic and spin-orbit coupling effects at the Douglas-Kroll level. The variational stability of the spin-orbit coupling operator was discussed in terms of the relativistic kinematic operators and depicted graphically. A detailed analysis of the spin-orbit multireference dissociation curves of the 6p element hydrides as well as of their atomic spectra allowed to establish the accuracy of the model core potentials with respect to all-electron calculations to be within several mA for r(e), meV (ceV) for D(e) at the correlation level of configuration interaction (multireference perturbation theory), 30 cm(-1) for omega(e), and about 350 cm(-1) for the low-lying atomic and molecular term and level energies. These values are expected to be the maximum error limits for the model core potentials of all the np-block elements (n=2-6). Furthermore, a good agreement with experiment requires that many terms be coupled in the spin-orbit coupling calculations. A timing study of Tl and TlH computations indicates that the model core potentials lead to 20-fold (6-fold) speedup at the level of configuration interaction (multireference perturbation theory) calculations.

New model core potentials for gold.

Four model core potentials (MCPs) for gold were developed using results from the third-order Douglas-Kroll-Hess relativistic all-electron calculations. The MCPs were developed with four different valence spaces, ranging from the 5p, 5d, and 6s orbitals to 5s, 4f, 5p, 5d, and 6s orbitals. The new MCPs were applied in the calculations of atomic properties and potential energy curves of AuH and Au(2). Results indicate that the 4f orbital may be excluded but the 5s orbital must be included in the valence space because of the importance of 5s-6s electron correlation. The model core potential that has the valence space comprising the 5s, 5p, 5d, and 6s orbitals is considered to be the most accurate and efficient of these new potentials.

Model core potentials for studies of scalar-relativistic effects and spin-orbit coupling at Douglas-Kroll level. I. Theory and applications to Pb and Bi.

A theory of model core potentials that can treat spin-orbit-coupling (SOC) effects at the level of Douglas-Kroll formalism has been developed. By storing the damping effect of kinematic operator in the Douglas-Kroll spin-orbit operator into an additional set of basis set contraction coefficients, the Breit-Pauli spin-orbit code in the GAMESS-US program was successfully used to perform Douglas-Kroll spin-orbit calculations. It was found that minute errors in the radial functions of valence orbitals lead to large errors in the spin-orbit energy levels and thus fitting the radial part of the spin-orbit matrix elements is necessary in model core potential parametrization. The first model core potentials that include the new formalism were developed for two 6p-block elements, Pb and Bi. The valence space of the 5p, 5d, 6s, and 6p orbitals was used because of the large SOC between the 5p and 6p orbitals. The model core potentials were validated in the calculations of atomic properties as well as spectroscopic constants of diatomic metal hydrides. The agreement between results of the model core potential and all-electron calculations was excellent, with energy errors of hundreds of cm(-1) and hundredths of eV, r(e) errors of thousandths of A, and omega(e) errors under 20 cm(-1). Two kinds of interplay between SOC effect and bonding process (antibonding and bonding SOC) were demonstrated using spin-free term potential curves of PbH and BiH. The present study is the first extension of the model core potential method beyond Breit-Pauli to Douglas-Kroll SOC calculations.

Mechanochemical synthesis of 0D and 3D cesium lead mixed halide perovskites.

A simplified mechanochemical synthesis approach for Cs-containing mixed halide perovskite materials of lower and higher dimensionality (0D and 3D, respectively) is presented with stoichiometric control from their halide salts, CsX and PbX2 (X = Cl, Br, I). Excellent optical bandgap tunability through halide substitution is supported by property measurements and changes to the materials' structure. Complementary NMR and XRD methods, along with support from DFT calculations, reveal highly crystalline 0D and 3D solid solutions with a complex arrangement of [PbX6-xXx']4- pseudooctahedra caused by halide distribution about the Pb centre.

Relativistic model core potential study of the Au+ Xe system.

A computational study of the Au(+)Xe ionic system has been performed using newly developed coupled-cluster methods and relativistic model core potentials, with extra basis functions optimized to afford superior polarizabilities. Potential energy curves for the dissociation of Au(+)Xe were studied at different levels of theory, and molecular properties (bond length and harmonic vibrational frequency) were calculated. Wave functions were analyzed using the natural bond orbital method. The nature of bonding in this system is discussed.

Anesthetic Alterations of Collective Terahertz Oscillations in Tubulin Correlate with Clinical Potency: Implications for Anesthetic Action and Post-Operative Cognitive Dysfunction.

Anesthesia blocks consciousness and memory while sparing non-conscious brain activities. While the exact mechanisms of anesthetic action are unknown, the Meyer-Overton correlation provides a link between anesthetic potency and solubility in a lipid-like, non-polar medium. Anesthetic action is also related to an anesthetic's hydrophobicity, permanent dipole, and polarizability, and is accepted to occur in lipid-like, non-polar regions within brain proteins. Generally the protein target for anesthetics is assumed to be neuronal membrane receptors and ion channels, however new evidence points to critical effects on intra-neuronal microtubules, a target of interest due to their potential role in post-operative cognitive dysfunction (POCD). Here we use binding site predictions on tubulin, the protein subunit of microtubules, with molecular docking simulations, quantum chemistry calculations, and theoretical modeling of collective dipole interactions in tubulin to investigate the effect of a group of gases including anesthetics, non-anesthetics, and anesthetic/convulsants on tubulin dynamics. We found that these gases alter collective terahertz dipole oscillations in a manner that is correlated with their anesthetic potency. Understanding anesthetic action may help reveal brain mechanisms underlying consciousness, and minimize POCD in the choice and development of anesthetics used during surgeries for patients suffering from neurodegenerative conditions with compromised cytoskeletal microtubules.