Biological control of S-nitrosothiol reactivity: potential role of sigma-hole interactions.

S-Nitrosothiols (RSNOs) are ubiquitous biomolecules whose chemistry is tightly controlled in vivo, although the specific molecular mechanisms behind this biological control remain unknown. In this work, we demonstrate, using high-level ab initio and DFT calculations, the ability of RSNOs to participate in intermolecular interactions with electron pair donors/Lewis bases (LBs) via a σ-hole, a region of positive electrostatic potential on the molecular surface at the extension of the N-S bond. Importantly, σ-hole binding is able to modulate the properties of RSNOs by changing the balance between two chemically opposite (antagonistic) resonance components, R-S[double bond, length as m-dash]N-O (D) and R-S/NO (I), which are, in addition to the main resonance structure R-S-N[double bond, length as m-dash]O, necessary to describe the unusual electronic structure of RSNOs.

Lewis Acid Coordination Redirects S-Nitrosothiol Signaling Output.

S-Nitrosothiols (RSNOs) serve as air-stable reservoirs for nitric oxide in biology. While copper enzymes promote NO release from RSNOs by serving as Lewis acids for intramolecular electron-transfer, redox-innocent Lewis acids separate these two functions to reveal the effect of coordination on structure and reactivity. The synthetic Lewis acid B(C F ) coordinates to the RSNO oxygen atom, leading to profound changes in the RSNO electronic structure and reactivity.

Redox-Induced Molecular Actuators: The Case of Oxy-Alternate Bridged Cyclotetraveratrylene.

We report a practical two-step approach for the synthesis of hybrid-bridge macrocyclic molecules that has been used to synthesize two novel oxy-alternate-bridged macrocyclic molecules, oxy-alternate cyclotetraveratrylene (CTTV) and oxy-alternate cyclohexaveratrylene (CHV). Electrochemistry, absorption spectroscopy, X-ray crystallography, and DFT calculations demonstrate that CTTV acts as a redox-induced molecular actuator, as its switches from the open conformation in the neutral state to the closed conformation in the cation-radical state.

Improving Performance of the SMD Solvation Model: Bondi Radii Improve Predicted Aqueous Solvation Free Energies of Ions and p Values of Thiols.

Calculation of the solvation free energy of ionic molecules is the principal source of errors in the quantum chemical evaluation of p values using implicit polarizable continuum solvent models. One of the important parameters affecting the performance of these models is the choice of atomic radii. Here, we assess the performance of the solvation model based on density (SMD) implicit solvation model employing SMD default radii (SMD) and Bondi radii (SMD-B), a set of empirical atomic radii developed based on the crystallographic data.

An Electron-Rich Calix[4]arene-Based Receptor with Unprecedented Binding Affinity for Nitric Oxide.

Calixarenes have found widespread application as building blocks for the design and synthesis of functional materials in host-guest chemistry. The ongoing desire to develop a detailed understanding of the nature of NO bonding to multichromophoric π-stacked assemblies led us to develop an electron-rich methoxy derivative of calix[4]arene (3), which we show exists as a single conformer in solution at ambient temperature. Here, we examine the redox properties of this derivative, generate its cation radical (3 ) using robust chemical oxidants, and determine the relative efficacy of its NO binding in comparison with model calixarenes.

Toward reliable modeling of S-nitrosothiol chemistry: Structure and properties of methyl thionitrite (CHSNO), an S-nitrosocysteine model.

Methyl thionitrite CHSNO is an important model of S-nitrosated cysteine aminoacid residue (CysNO), a ubiquitous biological S-nitrosothiol (RSNO) involved in numerous physiological processes. As such, CHSNO can provide insights into the intrinsic properties of the -SNO group in CysNO, in particular, its weak and labile S-N bond. Here, we report an ab initio computational investigation of the structure and properties of CHSNO using a composite Feller-Peterson-Dixon scheme based on the explicitly correlated coupled cluster with single, double, and perturbative triple excitations calculations extrapolated to the complete basis set limit, CCSD(T)-F12/CBS, with a number of additive corrections for the effects of quadruple excitations, core-valence correlation, scalar-relativistic and spin-orbit effects, as well as harmonic zero-point vibrational energy with an anharmonicity correction.

Modeling of S-Nitrosothiol-Thiol Reactions of Biological Significance: HNO Production by S-Thiolation Requires a Proton Shuttle and Stabilization of Polar Intermediates.

Nitroxyl (HNO), a reduced form of the important gasotransmitter nitric oxide, exhibits its own unique biological activity. A possible biological pathway of HNO formation is the S-thiolation reaction between thiols and S-nitrosothiols (RSNOs). Our density functional theory (DFT) calculations suggested that S-thiolation proceeds through a proton transfer from the thiol to the RSNO nitrogen atom, which increases electrophilicity of the RSNO sulfur, followed by nucleophilic attack by thiol, yielding a charge-separated zwitterionic intermediate structure RSS (R)N(H)O (Zi), which decomposes to yield HNO and disulfide RSSR.

Metallic-like bonding in plasma-born silicon nanocrystals for nanoscale bandgap engineering.

Based on ab initio molecular dynamics simulations, we show that small nanoclusters of about 1 nm size spontaneously generated in a low-temperature silane plasma do not possess tetrahedral structures, but are ultrastable. Apparently small differences in the cluster structure result in substantial modifications in their electric, magnetic, and optical properties, without the need for any dopants. Their non-tetrahedral geometries notably lead to electron deficient bonds that introduce efficient electron delocalization that strongly resembles the one of a homogeneous electron gas leading to metallic-like bonding within a semiconductor nanocrystal.

Electrostatic point charge fitting as an inverse problem: Revealing the underlying ill-conditioning.

Atom-centered point charge (PC) model of the molecular electrostatics-a major workhorse of the atomistic biomolecular simulations-is usually parameterized by least-squares (LS) fitting of the point charge values to a reference electrostatic potential, a procedure that suffers from numerical instabilities due to the ill-conditioned nature of the LS problem. To reveal the origins of this ill-conditioning, we start with a general treatment of the point charge fitting problem as an inverse problem and construct an analytical model with the point charges spherically arranged according to Lebedev quadrature which is naturally suited for the inverse electrostatic problem. This analytical model is contrasted to the atom-centered point-charge model that can be viewed as an irregular quadrature poorly suited for the problem.

A deeper insight into strain for the sila-bi[6]prismane ( Si18H12) cluster with its endohedrally trapped silicon atom, Si19H12.

A new family of over-coordinated hydrogenated silicon nanoclusters with outstanding optical and mechanical properties has recently been proposed. For one member of this family, namely the highly symmetric Si19 H12 nanocrystal, strain calculations have been presented with the goal to question its thermal stability and the underlying mechanism of ultrastability and electron-deficiency aromaticity. Here, the invalidity of these strain energy (SE) calculations is demonstrated mainly based on a fundamentally wrong usage of homodesmotic reactions, the miscounting of atomic bonds, and arithmetic errors.

Genetic algorithm optimization of point charges in force field development: challenges and insights.

Evolutionary methods, such as genetic algorithms (GAs), provide powerful tools for optimization of the force field parameters, especially in the case of simultaneous fitting of the force field terms against extensive reference data. However, GA fitting of the nonbonded interaction parameters that includes point charges has not been explored in the literature, likely due to numerous difficulties with even a simpler problem of the least-squares fitting of the atomic point charges against a reference molecular electrostatic potential (MEP), which often demonstrates an unusually high variation of the fitted charges on buried atoms. Here, we examine the performance of the GA approach for the least-squares MEP point charge fitting, and show that the GA optimizations suffer from a magnified version of the classical buried atom effect, producing highly scattered yet correlated solutions.

Structure, stability, and substituent effects in aromatic S-nitrosothiols: the crucial effect of a cascading negative hyperconjugation/conjugation interaction.

Aromatic S-nitrosothiols (RSNOs) are of significant interest as potential donors of nitric oxide and related biologically active molecules. Here, we address a number of poorly understood properties of these species via a detailed density functional theory and the natural bond orbital (NBO) investigation of the parent PhSNO molecule. We find that the characteristic perpendicular orientation of the -SNO group relative to the phenyl ring is determined by a combination of the steric factors and the donor-acceptor interactions including, in particular, a cascading orbital interaction involving electron delocalization from the oxygen lone pair to the σ-antibonding S-N orbital and then to the π*-aromatic orbitals, an unusual negative hyperconjugation/conjugation long-range delocalization pattern.

Key Role of End-Capping Groups in Optoelectronic Properties of Poly--phenylene Cation Radicals.

Poly--phenylenes (PPs) are prototype systems for understanding the charge transport in π-conjugated polymers. In a combined computational and experimental study, we demonstrate that the smooth evolution of redox and optoelectronic properties of PP cation radicals toward the polymeric limit can be significantly altered by electron-donating -alkyl and -alkoxy end-capping groups. A multiparabolic model (MPM) developed and validated here rationalizes this unexpected effect by interplay of the two modes of hole stabilization: due to the framework of equivalent -phenylene units and due to the electron-donating end-capping groups.

On the possible biological relevance of HSNO isomers: a computational investigation.

Thionitrous acid (HSNO), the smallest S-nitrosothiol, has been identified as a potential biologically active molecule that connects the biochemistries of two important gasotransmitters, nitric oxide (NO) and hydrogen sulfide (H2S). Here, we computationally explore possible isomerization reactions of HSNO that may occur under physiological conditions using high-level coupled-cluster as well as density functional theory and composite CBS-QB3 methodology calculations. Gas-phase calculations show that the formation of the tautomeric form HONS and the Y-isomer SN(H)O is thermodynamically feasible, as they are energetically close, within ∼6 kcal mol(-1), to HSNO, while the recently proposed three-membered ring isomer is not thermodynamically or kinetically accessible.

Photoexcitation and charge-transfer-to-solvent relaxation dynamics of the I(-)(CH3CN) complex.

Photoexcitation of iodide-acetonitrile clusters, I(-)(CH3CN)n, to the charge-transfer-to-solvent (CTTS) state and subsequent cluster relaxation could result in the possible formation of cluster analogues of the bulk solvated electron. In this work, the relaxation process of the CTTS excited iodide-acetonitrile binary complex, [I(-)(CH3CN)]*, is investigated using rigorous ab initio quantum chemistry calculations and direct-dynamics simulations to gain insight into the role and motion of iodine and acetonitrile in the relaxation of CTTS excited I(-)(CH3CN)n. Computed potential energy curves and profiles of the excited electron vertical detachment energy for [I(-)(CH3CN)]* along the iodine-acetonitrile distance coordinate reveal for the first time significant dispersion effects between iodine and the excited electron, which can have a significant stabilizing effect on the latter.

Computational design of S-nitrosothiol "click" reactions.

To address a long-standing problem of finding efficient reactions for chemical labeling of protein-based S-nitrosothiols (RSNOs), we computationally explored hitherto unknown (3+2) cycloaddition RSNO reactions with alkynes and alkenes. Nonactivated RSNO cycloaddition reactions have high activation enthalpy (>20 kcal/mol at the CBS-QB3 level) and compete with alternative S-N bond insertion pathway. However, the (3+2) cycloaddition reaction barriers can be dramatically lowered by coordination of a Lewis acid to the N atom of the -SNO group.

Unprecedented External Electric Field Effects on S-Nitrosothiols: Possible Mechanism of Biological Regulation?

Reactions of S-nitrosothiols (RSNOs), ubiquitous carriers of nitric oxide NO and its physiological activity, are tightly regulated in biological systems, but the mechanisms of this regulation are not well understood. Here, we computationally demonstrate that RSNO properties can be dramatically altered by biologically accessible external electric fields (EEFs) by modulation of the two minor antagonistic resonance structures of RSNOs, which have opposite formal charge distributions and bonding patterns. As these resonance contributions relate to the two competing modes of RSNO reactivity with nucleophiles, via N- or S-atom directed nucleophilic attack, EEFs are predicted to be efficient in controlling biologically important RSNO reactions with thiols.

Protein control of S-nitrosothiol reactivity: interplay of antagonistic resonance structures.

There is currently great interest in S-nitrosothiols (RSNOs) because formation of protein-based RSNOs-protein S-nitrosation-has been recently recognized as a major pathway of the biological function of nitric oxide, NO. Despite the growing number of S-nitrosated proteins identified in vivo, enzymatic processes that control reactions of biological RSNOs are still not well understood. In this article, we use a range of models to computationally demonstrate that specific interactions of RSNOs with charged and polar residues in proteins can result in dramatic modification of RSNO structure, stability, and reactivity.

No longer a complex, not yet a molecule: a challenging case of nitrosyl O-hydroxide, HOON.

HOON might be an elusive intermediate of atmospheric photochemical reactions of HONO or recombination of the parent nitrene HN and molecular oxygen. However, no reliable data on HOON structure and stability are available, and the nature of the O-O bond is not well understood. In this study, we used high-level single- [CCSD(T) and, CCSDTQ] and multireference [CASPT2, MR-AQCC] ab initio calculations to determine properties of HOON: geometry, harmonic and anharmonic vibrational frequencies, thermodynamic stability, and electronic structure.

Photochemical electrocyclic ring closure and leaving group expulsion from N-(9-oxothioxanthenyl)benzothiophene carboxamides.

N-(9-Oxothioxanthenyl)benzothiophene carboxamides bearing leaving groups (LG(-) = Cl(-), PhS(-), HS(-), PhCH(2)S(-)) at the C-3 position of the benzothiophene ring system photochemically cyclize with nearly quantitative release of the leaving group, LG(-). The LG(-) photoexpulsions can be conducted with 390 nm light or with a sunlamp. Solubility in 75% aqueous CH(3)CN is achieved by introducing a carboxylate group at the C-6 position of the benzothiophene ring.

Photoinduced electron transfer and solvation dynamics in aqueous clusters: comparison of the photoexcited iodide-water pentamer and the water pentamer anion.

Upon photoexcitation of iodide-water clusters, I(-)(H(2)O)(n), an electron is transferred from iodide to a diffuse cluster-supported, dipole-bound orbital. Recent femtosecond photoelectron spectroscopy experiments have shown that, for photoexcited I(-)(H(2)O)(n) (n≥ 5), complex excited-state dynamics ultimately result in the stabilization of the transferred electron. In this work, ab initio molecular dynamics simulations of excited-state I(-)(H(2)O)(5) and (H(2)O)(5)(-) are performed, and the simulated time evolution of their structural and electronic properties are compared to determine unambiguously the respective roles of the water molecules and the iodine atom in the electron stabilization dynamics.

Can a dipole-bound electron form a pseudo-atom? An atoms-in-molecules study of the hydrated electron.

Non-nuclear local maxima, or attractors, of electron density are a rare but very interesting feature of the electron density distribution in molecules and solids. Recently, non-nuclear attractors (NNAs) and the corresponding pseudoatoms of electron density have been identified with the quantum theory of atoms in molecules for some anionic clusters formed by several polar solvent molecules and an excess electron bound in either a solvated-electron or dipole-bound fashion. This contribution reports a detailed study of the topology of the electron density for a series of dipole-bound water cluster anions, as calculated with Hartree-Fock, Møller-Plesset perturbation theory, and coupled-cluster methods together with basis sets augmented with extra diffuse basis functions to accommodate the excess electron.

Kinetics and mechanism of S-nitrosothiol acid-catalyzed hydrolysis: sulfur activation promotes facile NO+ release.

The denitrosation of three primary S-nitrosothiols (RSNO; S-nitrosocysteine, S-nitroso-N-acetylcysteine, and S-nitrosoglutathione) and two tertiary RSNOs (S-nitrosopenicillamine and S-nitroso-N-acetylpenicillamine) was investigated in 3.75 M H(2)SO(4) to probe the mechanism of acid-catalyzed RSNO hydrolysis and its dependence on RSNO structure. This reversible reaction was forced to proceed in the denitrosation direction by trapping the nitrosating agent with HN(3).

Mechanically induced generation of highly reactive excited-state oxygen molecules in cluster scattering.

Molecular electronic excitation in (O(2))(n) clusters induced by mechanical collisions via the "chemistry with a hammer" is investigated by a combination of molecular dynamics simulations and quantum chemistry calculations. Complete active space self-consistent field augmented with triple-zeta polarizable basis set quantum chemistry calculations of a compressed (O(2))(2) cluster model in various configurations reveal the emergence of possible pathways for the generation of electronically excited singlet O(2) molecules upon cluster compression and vibrational excitation, due to electronic curve-crossing and spin-orbit coupling. Extrapolation of the model (O(2))(2) results to larger clusters suggests a dramatic increase in the population of electronically excited O(2) products, and may account for the recently observed cluster-catalyzed oxidation of silicon surfaces, via singlet oxygen generation induced by cluster impact, followed by surface reaction of highly reactive singlet O(2) molecules.

Structure and stability of HSNO, the simplest S-nitrosothiol.

High-level ab initio calculations employing the CCSD and CCSD(T) coupled cluster methods with a series of systematically convergent correlation-consistent basis sets have been performed to obtain accurate molecular geometry and energetic properties of the simplest S-nitrosothiol (RSNO), HSNO. The properties of the S-N bond, which are central to the physiological role of RSNOs in the storage and transport of nitric oxide, are highlighted. Following corrections for quadruple excitations, core-valence correlation and relativistic effects, the CCSD(T) method extrapolated to the complete basis set (CBS) limit yielded values of 1.