Toward Reliable Modeling of S-nitrosothiol Chemistry: Structure and Properties of Methyl Thionitrite (CH3SNO), an S-nitrosocysteine Model

Methyl thionitrite CH3SNO is an important model of S-nitrosated cysteine aminoacid residue (CysNO), a ubiquitous biological S-nitrosothiol (RSNO) involved in numerous physiological processes. As such, CH3SNO 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 CH3SNO 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. These calculations suggest that the S—N bond in CH3SNO is significantly elongated (1.814 Å) and has low stretching frequency and dissociation energy values, νS—N = 387 cm−1 and D0 = 32.4 kcal/mol. At the same time, the S—N bond has a sizable rotation barrier, △ role= presentation style= display: inline; font-style: normal; font-weight: normal; line-height: normal; font-size: 20px; text-indent: 0px; text-align: left; text-transform: none; letter-spacing: normal; word-spacing: normal; word-wrap: normal; white-space: nowrap; float: none; direction: ltr; max-width: none; max-height: none; min-width: 0px; min-height: 0px; border: 0px; padding: 0px 2px 0px 0px; margin: 0px; position: relative; \u3e△△E0≠ role= presentation style= display: inline; font-style: normal; font-weight: normal; line-height: normal; font-size: 12px; text-indent: 0px; text-align: left; text-transform: none; letter-spacing: normal; word-spacing: normal; word-wrap: normal; white-space: nowrap; float: none; direction: ltr; max-width: none; max-height: none; min-width: 0px; min-height: 0px; border: 0px; padding: 0px 2px 0px 0px; margin: 0px; position: relative; \u3e≠≠ = 12.7 kcal/mol, so CH3SNO exists as a cis- or trans-conformer, the latter slightly higher in energy, △ role= presentation style= display: inline; font-style: normal; font-weight: normal; line-height: normal; font-size: 20px; text-indent: 0px; text-align: left; text-transform: none; letter-spacing: normal; word-spacing: normal; word-wrap: normal; white-space: nowrap; float: none; direction: ltr; max-width: none; max-height: none; min-width: 0px; min-height: 0px; border: 0px; padding: 0px 2px 0px 0px; margin: 0px; position: relative; \u3e△△E0 = 1.2 kcal/mol. The S—N bond properties are consistent with the antagonistic nature of CH3SNO, whose resonance representation requires two chemically opposite (antagonistic) resonance structures, CH3—S+=N—O−and CH3—S−/NO+, which can be probed using external electric fields and quantified using the natural resonance theory approach (NRT). The calculated S—N bond properties slowly converge with the level of correlation treatment, with the recently developed distinguished cluster with single and double excitations approximation (DCSD-F12) performing significantly better than the coupled cluster with single and double excitations (CCSD-F12), although still inferior to the CCSD(T)-F12 method that includes perturbative triple excitations. Double-hybrid density functional theory (DFT) calculations with mPW2PLYPD/def2-TZVPPD reproduce well the geometry, vibrational frequencies, and the S—N bond rotational barrier in CH3SNO, while hybrid DFT calculations with PBE0/def2-TZVPPD give a better S—N bond dissociation energy

Electrostatic Point Charge Fitting as an Inverse Problem: Revealing the Underlying Ill-Conditioning

Atom-centered point charge 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. Here, 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 analytically soluble model with the point charges spherically arranged according to Lebedev quadrature 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. This analysis shows that the numerical problems of the point charge fitting are due to the decay of the curvatures corresponding to the eigenvectors of LS sum Hessian matrix. In part, this ill-conditioning is intrinsic to the problem and related to decreasing electrostatic contribution of the higher multipole moments, that are, in the case of Lebedev grid model, directly associated with the Hessian eigenvectors. For the atom-centered model, this association breaks down beyond the first few eigenvectors related to the high-curvature monopole and dipole terms; this leads to even wider spread-out of the Hessian curvature values. Using these insights, it is possible to alleviate the ill-conditioning of the LS point-charge fitting without introducing external restraints and/or constraints. Also, as the analytical Lebedev grid PC model proposed here can reproduce multipole moments up to a given rank, it may provide a promising alternative to including explicit multipole terms in a force field

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. This effect can be understood in terms of the linearly independent, natural coordinates of the MEP fitting problem defined by the eigenvectors of the least-squares sum Hessian matrix, which are also equivalent to the eigenvectors of the covariance matrix evaluated for the scattered GA solutions. GAs quickly converge with respect to the high-curvature coordinates defined by the eigenvectors related to the leading terms of the multipole expansion, but have difficulty converging with respect to the low-curvature coordinates that mostly depend on the buried atom charges. The performance of the evolutionary techniques dramatically improves when the point charge optimization is performed using the Hessian or covariance matrix eigenvectors, an approach with a significant potential for the evolutionary optimization of the fixed-charge biomolecular force fields

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−, PhCH2S−) 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 CH3CN is achieved by introducing a carboxylate group at the C-6 position of the benzothiophene ring. The carboxylate and methyl ester derivatives regiospecifically cyclize at the more hindered C-1 position of the thioxanthone ring. Otherwise, the photocyclization favors the C-3 position of the thioxanthone. Quantum yields for reaction are 0.01–0.04, depending on LG− basicity. Electronic structure calculations for the triplet excited state show that excitation transfer occurs from the thioxanthone to the benzothiophene ring. Subsequent cyclization in the triplet excited state is energetically favourable and initially generates the triplet excited state of the zwitterionic species. Expulsion of LG− is thought to occur once this species converts to the closed shell ground state

Structure, Stability, and Substituent Effects in Aromatic \u3cem\u3eS\u3c/em\u3e-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. These interactions, which are also responsible for the relative weakness of the S–N bond in PhSNO and the modulation of −SNO group properties in substituted aromatic RSNOs, can be interpreted as a resonance stabilization of the ionic resonance component RS–/NO+ of the RSNO electronic structure by the aromatic ring, similar to the resonance stabilization of PhS– anion. These insights into the chemistry and structure–property relationships in aromatic RSNOs can provide an important theoretical foundation for rational design of new RSNOs for biomedical applications

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. This unprecedented sensitivity of the −SNO group toward interactions with charged species is related to their unusual electronic structure that can be elegantly expressed in terms of antagonistic resonance structures. We propose a ‘ligand effect map’ (LEM) approach as an efficient way to estimate the environment effects on the −SNO groups in proteins without performing electronic structure calculations. Furthermore, the calculated 15N NMR signatures of these specific interactions suggest that 15N NMR spectroscopy can be an effective technique to identify and study these interactions experimentally. Overall, the results of this study suggest that RSNO reactions in vivo should be tightly controlled by the protein environment via modulation of the RSNO electronic structure

A Deeper Insight into Strain for the Sila-bi[6]prismane (Si\u3csub\u3e18\u3c/sub\u3eH\u3csub\u3e12\u3c/sub\u3e) Cluster with its Endohedrally Trapped Silicon Atom, Si\u3csub\u3e19\u3c/sub\u3eH\u3csub\u3e12\u3c/sub\u3e

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 Si19H12 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. Since the article in question is entirely anchored on those erroneous SE values, all of its conclusions and predictions become without meaning. We provide evidence here that the nanocrystal in question suffers from such low levels of strain that its thermodynamical stability should be largely sufficient for device fabrication in a realistic plasma reactor. Most remarkably, the two “alternative,” irregular isomers explicitly proposed in the aforementioned article are also electron-deficient, nontetrahedral, ultrastable, and aromatic nicely underlining the universality of the ultrastability concept for nanometric hydrogenated silicon clusters. © 2015 Wiley Periodicals, Inc

Improving Performance of the SMD Solvation Model: Bondi Radii Improve Predicted Aqueous Solvation Free Energies of Ions and pK\u3csub\u3ea\u3c/sub\u3e Values of Thiols

Calculation of the solvation free energy of ionic molecules is the principal source of errors in the quantum chemical evaluation of pKa 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. For a set of 112 ions (60 anions and 52 cations), the SMD-B model showed lower mean unsigned error (MUE) for predicted aqueous solvation free energies (4.0 kcal/mol for anions and 2.4 kcal/mol for cations) compared to the standard SMD model (MUE of 5.0 kcal/mol for anions and 2.9 kcal/mol for cations). In particular, usage of Bondi radii improves the aqueous solvation energies of sulfur-containing ions by \u3e5 kcal/mol compared to the SMD default radii. Indeed, for a set of 45 thiols, the SMD-B model was found to dramatically improve the predicted pKa values, with ∼1 pKa unit mean deviation from the experimental values, compared to ∼7 pKa units mean deviation for the SMD model with the default radii. These findings highlight the importance of the choice of atomic radii on the performance of the implicit solvation models

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. We find that 3/3+. is a remarkable receptor for NO+/NO, with unprecedented binding efficacy. The availability of precise experimental structures of this calixarene derivative and its NO complex, obtained by X‐ray crystallography, is critically important both for developing novel functional NO biosensors, and understanding the role of stacked aromatic donors in efficient NO binding, which may have relevance to biological NO transport

No Longer a Complex, Not Yet a Molecule: A Challenging Case of Nitrosyl O-Hydroxide, HOON

N-(9-Oxothioxanthenyl)benzothiophene carboxamides bearing leaving groups (LG− = Cl−, PhS−, HS−, PhCH2S−) 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 CH3CN is achieved by introducing a carboxylate group at the C-6 position of the benzothiophene ring. The carboxylate and methyl ester derivatives regiospecifically cyclize at the more hindered C-1 position of the thioxanthone ring. Otherwise, the photocyclization favors the C-3 position of the thioxanthone. Quantum yields for reaction are 0.01–0.04, depending on LG− basicity. Electronic structure calculations for the triplet excited state show that excitation transfer occurs from the thioxanthone to the benzothiophene ring. Subsequent cyclization in the triplet excited state is energetically favourable and initially generates the triplet excited state of the zwitterionic species. Expulsion of LG− is thought to occur once this species converts to the closed shell ground state