High Accuracy ab Initio Calculations on Reactions of OH with 1-Alkenes. The Case of Propene

The energetics of terminal, central OH-additions as well as allylic H-abstractions by OH in its reaction with propene was studied as proxies for the 1-alkenes + OH reactions using several single and multireference ab initio techniques with basis set extrapolation where possible. Selection of the localized occupied orbitals forming the active space for multireference methods is discussed. Initial geometries of the reactants, prereaction complex (π-complex), and transition states were determined at the [5,5]-CASPT2/cc-pVTZ level of theory. Frequency analysis was also carried out at this level with the introduction of a scale factor. Analyzing the results, it will be concluded that multireference effects are negligible, and from the various single reference models we will opt for UCCSD(T)/cc-pVTZ for final geometry optimizations and vibrational frequency analysis. These results will be compared with those from approximate models yielding information on the reliability of the latter. Triples contributions are found to be very important, except for the π-complex, which has a UCCSD(T)/CBS relative enthalpy of −10.56 kJ/mol compared to infinitely separated propene + OH. The addition transition states are found to have relative enthalpies of −9.93 kJ/mol for the central and −9.84 kJ/mol for the terminal case. Allylic abstraction mechanisms, although lying significantly higher, still have only slightly positive barriers - a value of 3.21 kJ/mol for the direct and 1.67 kJ/mol for the consecutive case. Conventional transition state theory was used as a rough estimation for determining rate constants and turned out to agree well with experimental data

Computational Elucidation of the Solvent-Dependent Addition of 4‑Hydroxy-2-nonenal (HNE) to Cysteine and Cysteinate Residues

The lipid peroxidation end product, 4-hydroxy-2-nonenal (HNE), is a secondary mediator of oxidative stress due to its strong ability to form adducts to the side chains of lysine, histidine, and cysteine residues (Cys) at increasing reactivities. This reaction can take place in various cellular environments and may be dependent on solvent. Moreover, approximately 10% of cysteine residues within the cells exist as the negatively charged cysteinate, which may also have a distinct reactivity toward HNE. In this study, quantum chemical calculations are used to investigate the reactivity of HNE toward Cys and cysteinate in three distinct solvent environments to mimic the aqueous, polar, and hydrophobic regions within the cell. Water enhances the reactivity of HNE to cysteine compared to that of the polar and hydrophobic solvents, and the reactivity of HNE is further augmented when Cys is first ionized to cysteinate. This is also confirmed by the transition state rate constant calculations. This study reveals the role of solvent polarity in these reactions and how cysteinate can account for the seemingly high reactivity of HNE toward Cys compared to other amino acid residues and demonstrates how a strong nucleophile can enhance the reactivity of an antioxidant analogue of the Cys residue

Glutathione as a Prebiotic Answer to α‑Peptide Based Life

The energetics of peptide bond formation is an important factor not only in the design of chemical peptide synthesis, but it also has a role in protein biosynthesis. In this work, quantum chemical calculations at 10 different levels of theory including G3MP2B3 were performed on the energetics of glutathione formation. The strength of the peptide bond is found to be closely related to the acid strength of the to-be N-terminal and the basicity of the to-be C-terminal amino acid. It is shown that the formation of the first peptide activates the amino acid for the next condensation step, manifested in bacterial protein synthesis where the first step is the formation of an N-formylmethionine dipeptide. The possible role of glutathione in prebiotic molecular evolution is also analyzed. The implications of the thermodynamics of peptide bond formation in prebiotic peptide formation as well as in the preference of α- instead of β- or γ-amino acids are discussed. An empirical correction is proposed for the compensation of the error due to the incapability of continuum solvation models in describing the change of the first solvation shell when a peptide bond is formed from two zwitterions accompanied by the disappearance of one ion pair

Molecular Dynamics Simulation at High Sodium Chloride Concentration: Toward the Inactive Conformation of the Human Adenosine A2A Receptor

The recently solved crystal structure of the human adenosine A2A receptor (hA2AR) shows the characteristics of a partially activated state. Experimental data suggests that high sodium chloride concentration shifts hA2AR to the inactive state. We found that molecular dynamics simulations at high sodium chloride concentration result in an inactive form of hA2AR reflected in the reformation of the “ionic lock” (Arg¹⁰²(3.50)−Glu²²⁸(6.30)) as well as in the reduction of the αC−αC distance between the intracellular sides of transmembrane helices 3 and 6 (TM3 and TM6). Interestingly, no such stabilization effect was observed at physiological concentrations. Our results suggest that the effect of high sodium chloride concentration might be exploited to generate an inactive state of hA2AR, which is more favorable for identifying pharmacologically relevant antagonists or inverse agonists

Multiscale Modeling of Interfacial Oxidation Mechanism at Air/Organic Interface: Reactions of CH₂CH-Terminated Self-Assembled Monolayer with OH^•, O₃, and HO₂^•

The first few elementary steps of the reactions of a structurally characterized CH₂CH-terminated self-assembled monolayer (SAM) with reactive oxygen species, such as OH^•, HO₂^•, and O₃ were investigated using the multilayer first principle technique (ONIOM­[QCISD­(T)/cc-pVTZ:MP2/6-311G­(d,p):BHandHLYP/6-31G­(d)]//ONIOM­[BHandHLYP/6-311G­(d,p):BHandHLYP/6-31G­(d)]) as a proxy for the interfacial oxidation mechanism on organic aerosol surfaces. The energetics of the reactions is compared with the analogous QCISD­(T)/cc-pVTZ//BHandHLYP/6-311G­(d,p) gas-phase results, to measure the energetic consequences of the presence of the surrounding alkene chains. All of the reactions studied are affected in such a way that the relative energies of the interfacial reactions became lower by the average value of 11.5 ± 6.1 kJ/mol than the corresponding gas-phase values. Because of this effect, interfacial H-abstractions by OH^• on both allylic and vinylic positions have submerged barriers (Δ<i>E</i>₀^‡ = −5.4 kJ/mol and Δ<i>E</i>₀^‡ = −5.8 kJ/mol, respectively). Also, the relative energy of the transition state of the C–C bond scission reaction started from the nonterminal adduct becoming negative (Δ<i>E</i>₀ = −0.8 kJ/mol). The latter channel can result in a release of vinyl alcohol and formation of alkyl radical-bearing SAM. Such lowering of the energy barriers might enhance the overall oxidation rate and change the branching ratio of the atmospheric oxidation of the unsaturated compound by OH^• at the interface compared to the gas-phase analogues. Because of the importance of prereaction complexes, the possible orientations of the adsorbed reactive oxygen species on the surface are also investigated, and O–H band shifts significantly toward lower wavenumbers in the IR spectra for the OH^• and HO₂^• complexes compared to the gas-phase band, which might be used later for the detection of these species at the interface if their lifetime is accessible for such spectroscopy

Atropisomerism of the Asn α Radicals Revealed by Ramachandran Surface Topology

C radicals are typically trigonal planar and thus achiral, regardless of whether they originate from a chiral or an achiral C-atom (e.g., C–H + ^•OH → C• + H₂O). <b>Oxidative stress</b> could initiate radical formation in proteins when, for example, the H-atom is abstracted from the Cα-carbon of an amino acid residue. Electronic structure calculations show that such a radical remains achiral when formed from the achiral Gly, or the chiral but small Ala residues. However, when longer side-chain containing proteogenic amino acid residues are studied (e.g., Asn), they provide radicals of axis chirality, which in turn leads to <b>atropisomerism</b> observed for the first time for peptides. The two <b>enantiomeric</b> extended backbone <b>structures</b>, •β_L and •β_D, interconvert via a pair of <b>enantiotopic reaction paths</b>, monitored on a 4D Ramachandran surface, with two distinct transition states of very different <i>Gibbs</i>-free energies: 37.4 and 67.7 kJ/mol, respectively. This discovery requires the reassessment of our understanding on radical formation and their conformational and stereochemical behavior. Furthermore, the atropisomerism of proteogenic amino acid residues should affect our understanding on radicals in biological systems and, thus, reframes the role of the D-residues as markers of <b>molecular aging</b>