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.

Benchmark ab initio and dynamical characterization of the stationary points of reactive atom + alkane and SN2 potential energy surfaces.

We describe a composite ab initio approach to determine the best technically feasible relative energies of stationary points considering additive contributions of the CCSD(T)/complete-basis-set limit, core and post-CCSD(T) correlation, scalar relativistic and spin-orbit effects, and zero-point energy corrections. The importance and magnitude of the different energy terms are discussed using examples of atom/ion + molecule reactions, such as X + CH4/C2H6 and X- + CH3Y/CH3CH2Cl [X, Y = F, Cl, Br, I, OH, etc.]. We test the performance of various ab initio levels and recommend the modern explicitly-correlated CCSD(T)-F12 methods for potential energy surface (PES) developments. We show that the choice of the level of electronic structure theory may significantly affect the reaction dynamics and the CCSD(T)-F12/double-zeta PESs provide nearly converged cross sections. Trajectory orthogonal projection and an Eckart-transformation-based stationary-point assignment technique are proposed to provide dynamical characterization of the stationary points, thereby revealing front-side complex formation in SN2 reactions and transition probabilities between different stationary-point regions.

Uncovering the role of the stationary points in the dynamics of the F- + CH3I reaction.

We describe an analysis method which assigns geometries to stationary points along (quasi)classical trajectories. The method is applied to the F- + CH3I reaction, thereby uncovering the role of the minima and transition states in the dynamics of the SN2 inversion, SN2 retention via front-side attack and double inversion, induced inversion, and proton-transfer channels. Stationary-point probability distributions, stationary-point-specific trajectory orthogonal projections, root-mean-square distance distributions, transition probability matrices, and time evolutions of the stationary points reveal long-lived front-side (F-ICH3) and hydrogen-bonded (F-HCH2I) complexes in the entrance channel and significant post-reaction ion-dipole complex (FCH3I-) formation in the SN2 exit channel. Most of the proton-transfer stationary points (FHCH2I-) participate in all the reaction channels with larger distance deviations than the double-inversion transition state. Significant forward-backward transitions are observed between the minima and transition states indicating complex, indirect dynamics. The utility of distance and energy constraints is also investigated, thereby restricting the assignment into uniform configuration or energy ranges around the stationary points.

High-Level-Optimized Stationary Points for the F-(H2O) + CH3I System: Proposing a New Water-Induced Double-Inversion Pathway.

We report 29 stationary points for the F-(H2O) + CH3I reaction obtained by using the high-level explicitly correlated CCSD(T)-F12b method with the aug-cc-pVDZ basis set for the determination of the benchmark structures and frequencies and the aug-cc-pVQZ basis for energy computations. The stationary points characterize the monohydrated F-- and OH--induced Walden-inversion pathways and, for the first time, the front-side attack and F--induced double-inversion mechanisms leading to CH3F with retention as well as the novel H2O-induced double-inversion retention pathway producing CH3OH. Hydration effectively increases the relative energies of the stationary points, but the monohydrated inversion pathways are still barrierless, whereas the front-side attack and double-inversion barrier heights are around 30 and 20 kcal/mol, respectively.

Mode-Specific Quasiclassical Dynamics of the F- + CH3I SN2 and Proton-Transfer Reactions.

Mode-specific quasiclassical trajectory computations are performed for the F- + CH3I( v k = 0, 1) SN2 and proton-transfer reactions at nine different collision energies in the range of 1.0-35.3 kcal/mol using a full-dimensional high-level ab initio analytical potential energy surface with ground-state and excited CI stretching ( v3), CH3 rocking ( v6), CH3 umbrella ( v2), CH3 deformation ( v5), CH symmetric stretching ( v1), and CH asymmetric stretching ( v4) initial vibrational modes. Millions of trajectories provide statistically definitive mode-specific cross sections, opacity functions, scattering angle distributions, and product internal energy distributions. The excitation functions reveal slight vibrational SN2 inversion inhibition/enhancement at low/high collision energies ( Ecoll), whereas large decaying-with- Ecoll vibrational enhancement effects for the SN2 retention (double inversion) and proton-transfer channels. The most efficient vibrational enhancement is found by exciting the CI stretching (high Ecoll) for SN2 inversion and the CH stretching modes (low Ecoll) for double inversion and proton transfer. Mode-specific effects do not show up in the scattering angle distributions and do blue-shift the hot/cold SN2/proton-transfer product internal energies.

Stretching vibration is a spectator in nucleophilic substitution.

How chemical reactions are influenced by reactant vibrational excitation is a long-standing question at the core of chemical reaction dynamics. In reactions of polyatomic molecules, where the Polanyi rules are not directly applicable, certain vibrational modes can act as spectators. In nucleophilic substitution reactions, CH stretching vibrations have been considered to be such spectators. While this picture has been challenged by some theoretical studies, experimental insight has been lacking. We show that the nucleophilic substitution reaction of F- with CH3I is minimally influenced by an excitation of the symmetric CH stretching vibration. This contrasts with the strong vibrational enhancement of the proton transfer reaction measured in parallel. The spectator behavior of the stretching mode is supported by both quasi-classical trajectory simulations and the Sudden Vector Projection model.

Effects of the Level of Electronic Structure Theory on the Dynamics of the F- + CH3I Reaction.

Accuracy of the different levels of electronic structure theory is frequently studied for stationary-point properties; however, little is known about the effects of the electronic structure methods and basis sets on the dynamics of chemical reactions. Here we report such an investigation for the F- + CH3I SN2 and proton-transfer reactions by developing 20 different analytical potential energy surfaces (PESs) obtained at the HF/DZ, HF/TZ, HF-D3(BJ)/DZ, HF-D3(BJ)/TZ, MP2/DZ, MP2/TZ, MP2-F12/DZ, MP2-F12/TZ, CCSD/DZ, CCSD-F12b/DZ, CCSD(T)/DZ, CCSD(T)-F12b/DZ, OQVCCD(T)/DZ, B97-1/TZ, PBE0/TZ, PBE0-D3(BJ)/TZ, M06-2X/TZ, M06-2X-D3(0)/TZ, B2PLYP/TZ, and B2PLYP-D3(BJ)/TZ levels of theory, where DZ and TZ denote the aug-cc-pVDZ and aug-cc-pVTZ basis sets with a relativistic effective core potential and the corresponding bases for iodine. Millions of quasiclassical trajectories on these PESs reveal that (a) in the case of standard methods, increasing the basis from DZ to TZ decreases the SN2 cross sections by 20-30%; (b) the explicitly correlated F12 reactivity is converged with a DZ basis;

Deciphering Front-Side Complex Formation in SN2 Reactions via Dynamics Mapping.

Due to their importance in organic chemistry, the atomistic understanding of bimolecular nucleophilic substitution (SN2) reactions shows exponentially growing interest. In this publication, the effect of front-side complex (FSC) formation is uncovered via quasi-classical trajectory computations combined with a novel analysis method called trajectory orthogonal projection (TOP). For both F- + CH3Y [Y = Cl,I] reactions, the lifetime distributions of the F-···YCH3 front-side complex revealed weakly trapped nucleophiles (F-). However, only the F- + CH3I reaction features strongly trapped nucleophiles in the front-side region of the prereaction well. Interestingly, both back-side and front-side attack show propensity to long-lived FSC formation. Spatial distributions of the nucleophile demonstrate more prominent FSC formation in case of the F- + CH3I reaction compared to F- + CH3Cl. The presence of front-side intermediates and the broad spatial distribution in the back-side region may explain the indirect nature of the F- + CH3I reaction.

High-level ab initio potential energy surface and dynamics of the F- + CH3I SN2 and proton-transfer reactions.

Bimolecular nucleophilic substitution (SN2) and proton transfer are fundamental processes in chemistry and F- + CH3I is an important prototype of these reactions. Here we develop the first full-dimensional ab initio analytical potential energy surface (PES) for the F- + CH3I system using a permutationally invariant fit of high-level composite energies obtained with the combination of the explicitly-correlated CCSD(T)-F12b method, the aug-cc-pVTZ basis, core electron correlation effects, and a relativistic effective core potential for iodine. The PES accurately describes the SN2 channel producing I- + CH3F via Walden-inversion, front-side attack, and double-inversion pathways as well as the proton-transfer channel leading to HF + CH2I-. The relative energies of the stationary points on the PES agree well with the new explicitly-correlated all-electron CCSD(T)-F12b/QZ-quality benchmark values. Quasiclassical trajectory computations on the PES show that the proton transfer becomes significant at high collision energies and double-inversion as well as front-side attack trajectories can occur. The computed broad angular distributions and hot internal energy distributions indicate the dominance of indirect mechanisms at lower collision energies, which is confirmed by analyzing the integration time and leaving group velocity distributions. Comparison with available crossed-beam experiments shows usually good agreement.

Continuous-flow solid-phase peptide synthesis: a revolutionary reduction of the amino acid excess.

A highly efficient continuous-flow technique for the synthesis of peptides was developed. The method allows the application of only 1.5 equivalents of amino acids during coupling, while yielding virtually quantitative conversions. A mesoscale reactor was constructed which permits the use of high temperature and pressure during the synthesis. A complete reaction parameter optimization was carried out. Under the optimum conditions, the couplings of all 20 proteinogenic amino acids were achieved with 1.5 amino acid equivalents with quantitative conversions. As a demonstration of the efficiency of the methodology, difficult sequences and ß-peptide foldamers with alicyclic side-chains were synthetized in excellent yields and with lower costs thanks to the lower amounts of amino acid and solvent used. By this the synthesis is highly economic and sustainable. Importantly, exotic and expensive artificial amino acids were incorporated into peptidic sequences by the utilization of a reasonable number of amino acid equivalents. The synthesis can be performed in quantities of microgram to gram in an automated way.