A novel mechanism of proton transfer in protonated peptides

The study presents quantum-chemical calculations on proton transfer in protonated N-acetylglycyl-N1-methylglycinamide (AGA) as a short oligopeptide model. All calculations employ the B3LYP functional and the 6-31++G** basis set. Two different mechanisms of proton transfer are discussed. The rate-determining step of the first mechanism exhibits an energy barrier of about 17.7 kcal mol-1, and it is represented by an isomerization of the proton around the double bond of the carbonyl group. The second mechanism is based on the large conformational flexibility of AGA, where all carbonyl oxygens cooperate. The rate-determining step of this mechanism exhibits an energy barrier of only 8.3 kcal mol-1.     

A computational study of intramolecular proton transfer in gaseous protonated glycine

The minimum energy paths for intramolecular proton transfer between the amino nitrogen and carbonyl oxygen atoms in gaseous protonated glycine were estimated at the Hartree-Fock (HF) and second-order M?ller-Plesset Perturbation (MP2) levels of theory. Potential energy profiles and their associated reactant, transition state, and product species calculated at the MP2/6-31G* level were shown to differ significantly from those obtained at the HF/6-31G* level. Effects of electron correlation and basis functions on the calculated geometries and energies of relevant species were examined at the HF, MP2, MP4, CCSD, and B3LYP levels using the 6-31G*, 6-31G**, 6-31+G**, 6-311+G**, 6-31+G(2d,2p), 6-311+G(3df,2p), cc-pVDZ, aug-cc-pVDZ, and cc-pVTZ basis sets. The HF and MP2 optimized levels with the 6-31G*, 6-31G**, 6-31+G**, and 6-311+G** bases were used to calculate the thermodynamic and kinetic properties of the proton transfer reaction at 298.15 K and 1 atm, which include enthalpy, entropy, Gibbs free energy, equilibrium constant, potential energy barriers, tunneling transmission coefficients, and rate constants. Results indicate that the proton in a carbonyl O-protonated glycine undergoes a rapid migration to the amino nitrogen atom, while the reverse process is extremely unfavorable. The objective of this work is to develop practical theoretical procedures for studying proton transfer reactions in amino acids and peptides and to assemble physical data from these model calculations for future references.     

A multiscale coarse-graining method for biomolecular systems

A new approach is presented for obtaining coarse-grained (CG) force fields from fully atomistic molecular dynamics (MD) trajectories. The method is demonstrated by applying it to derive a CG model for the dimyristoylphosphatidylcholine (DMPC) lipid bilayer. The coarse-graining of the interparticle force field is accomplished by an application of a force-matching procedure to the force data obtained from an explicit atomistic MD simulation of the biomolecular system of interest. Hence, the method is termed a "multiscale" CG (MS-CG) approach in which explicit atomistic-level forces are propagated upward in scale to the coarse-grained level. The CG sites in the lipid bilayer application were associated with the centers-of-mass of atomic groups because of the simplicity in the evaluation of the forces acting on them from the atomistic data. The resulting CG lipid bilayer model is shown to accurately reproduce the structural properties of the phospholipid bilayer.     

Vibrations of a chelated proton in a protonated tertiary diamine

Vibrational spectra of the conjugate acid of Me(2)NCH(2)CH(2)CH(2)CH(2)NMe(2) (N,N,N',N'-tetramethylputrescine) have been examined in the gaseous and crystalline phases using Infrared Multiple Photon Dissociation (IRMPD) spectroscopy, Inelastic Neutron Scattering (INS), and high pressure Raman spectroscopy. A band observed near 530 cm(-1) is assigned to the asymmetric stretch of the bridging proton between the two nitrogens, based on deuterium substitution and pressure dependence. The NN distance measured by X-ray crystallography gives a good match to DFT calculations, and the experimental band position agrees with the value predicted from theory using a 2-dimensional potential energy surface. The reduced dimensionality potential energy surface, which treats the ion as though it possesses a linear NHN geometry, shows low barriers to proton transit from one nitrogen to the other, with zero point levels close to the barrier tops. In contrast, two other related systems containing strong hydrogen bonds do not exhibit the same spectroscopic signature of a low barrier hydrogen bond (LBHB). On the one hand, the IRMPD spectra of the conjugate acid ions of the amino acid N,N,N',N'-tetramethylornithine (in which the two nitrogens have different basicities) show fewer bands and no comparable isotopic shifts in the low frequency domain. On the other hand, the IRMPD spectrum of the shorter homologue Me(2)NCH(2)CH(2)CH(2)NMe(2) (N,N,N',N'-tetramethyl-1,3-propanediamine), for which the NHN bond angle deviates substantially from linearity, displays more than one band in the 1100-1400 cm(-1) domain, which vanish as a consequence of deuteration.     

The proton affinity and the structure of protonated species of methylsilane

An ab initio LCAO-MO-SCF calculation was made on the proton affinity (PA ) of methylsilane (CH₃SiH₃) by using STO -3G, MIDI -1, and MIDI -1* basis sets. Three types of protonated methylsilane are taken into account, and their geometrical parameters are optimized. The calculated PA of CH₃SiH₃ is 160.5 kcal/mol, which exceeds that of SiH₄ by 11.5 kcal/mol. The protonated species (I) which refers to Si—C bond protonation is shown to be most favorable, and to be a weak σ-complex between CH₄ and SiH. Other two species are also σ-complexes between H₂ molecule and SiH₃CH or CH₃SiH, and similar to CH, SiH, GeH, and C₂H.     

A priori predictions of the rotational constants for protonated formaldehyde and protonated methanol

Protonated formaldehyde and protonated methanol are candidate interstellar molecules and models for classes of protonated oxygen compounds. Ab initio molecular orbital theory has been used to compute rotational constants to guide spectroscopic searches both in the laboratory and in space. The ab initio results are empirically corrected to account for systematic deficiencies in the theory and zero-point vibrational effects; they are expected to be accurate to approximately +/-2%. For H2COH+ the resultant constants are (in GHz) A = 194.3, B = 34.28, and C = 29.14; for H3COH2+ A = 103.7, B = 21.18, and C = 20.30.     

Inter- and intra-annular proton exchange in gaseous benzylbenzenium ions (protonated diphenylmethane)

Two distinct proton exchange reactions occur in metastable gaseous benzylbenzenium ions, generated by isobutane chemical ionization of diphenylmethane and four deuterium-labelled analogues. Whereas the proton ring-walk at the benzenium moiety is fast giving rise to a completely random intraannular proton exchange, the interannular proton exchange is surprisingly slow and competes with the elimination of benzene. A kinetic isotope effect of k_H/k_D= 5 has been determined for the interannular proton transfer, and a particularly high energy barrier of 50–75 kJ mol^?1 has been estimated. These observations are attributed to steric restrictions of the ring-to-ring proton transfer in benzylbenzenium ions and contrasted to the fast interannular proton exchange in the higher homologues.     

Additivity of proton and carbon nmr chemical shifts in protonated benzene carboxylic acids

The additivity of the proton and carbon chemical shift increments due to structural changes in a series of conjugate acids derived from benzene polycarboxylic acids is reported. In the acids, two sets of increments had been applied, one to the ortho diacids and one to acids which do not bear ortho substituents. In the conjugate acids only one set of increments is required. The disappearance of the ‘ortho’ effect may be the outcome of properties inherent to these conjugate acids.     

Electrochemical approach to concerted proton and electron transfers. Reduction of the water-superoxide ion complex

Concerted proton and electron transfers (CPET) currently attract considerable theoretical and experimental attention, notably in view of their likely involvement in many enzymatic reactions. Electrochemistry, through techniques such as cyclic voltammetry, can provide a quite effective access to CPET in terms of diagnosis and quantitative kinetic characterization. The relationships expressing the rate constant of an electrochemical CPET are given. Besides the CPET standard potential, it depends on two main factors. One is the reorganization energy, which appears as the sum of an intramolecular contribution and two solvent reorganization energies corresponding to proton and electron transfers, respectively. The other is the pre-exponential factor that mainly depends on proton tunneling through the activation barrier. Procedures for estimating these various factors as well as the H/D kinetic isotope effect are described. Application of the theory is illustrated by the experimental results obtained for the cyclic voltammetric reduction of the water-superoxide ion complex in dimethylformamide and acetonitrile.     

A novel salt bridge mechanism highlights the need for nonmobile proton conditions to promote disulfide bond cleavage in protonated peptides under low-energy collisional activation

The gas-phase fragmentation mechanisms of small models for peptides containing intermolecular disulfide links have been studied using a combination of tandem mass spectrometry experiments, isotopic labeling, structural labeling, accurate mass measurements of product ions, and theoretical calculations (at the MP2/6-311 + G(2d,p)//B3LYP/3-21G(d) level of theory). Cystine and its C-terminal derivatives were observed to fragment via a range of pathways, including loss of neutral molecules, amide bond cleavage, and S-S and C-S bond cleavages. Various mechanisms were considered to rationalize S-S and C-S bond cleavage processes, including charge directed neighboring group processes and nonmobile proton salt bridge mechanism. Three low-energy fragmentation pathways were identified from theoretical calculations on cystine N-methyl amide: (1) S-S bond cleavage dominated by a neighboring group process involving the C-terminal amide N to form either a protonated cysteine derivative or protonated sulfenyl amide product ion (44.3 kcal mol(-1)); (2) C-S bond cleavage via a salt bridge mechanism, involving abstraction of the alpha-hydrogen by the N-terminal amino group to form a protonated thiocysteine derivative (35.0 kcal mol(-1)); and (3) C-S bond cleavage via a Grob-like fragmentation process in which the nucleophilic N-terminal amino group forms a protonated dithiazolidine (57.9 kcal mol(-1)). Interestingly, C-S bond cleavage by neighboring group processes have high activation barriers (63.1 kcal mol(-1)) and are thus not expected to be accessible during low-energy CID experiments. In comparison to the energetics of simple amide bond cleavage, these S-S and C-S bond cleavage reactions are higher in energy, which helps rationalize why bond cleavage processes involving the disulfide bond are rarely observed for low-energy CID of peptides with mobile proton(s) containing intermolecular disulfide bonds. On the other hand, the absence of a mobile proton appears to "switch on" disulfide bond cleavage reactions, which can be rationalized by the salt bridge mechanism. This potentially has important ramifications in explaining the prevalence of disulfide bond cleavage in singly protonated peptides under MALDI conditions.     

Ortho‐hydroxyl effect and proton transfer via ion–neutral complex: the fragmentation study of protonated imine resveratrol analogues in mass spectrometry

The fragmentation pathways of protonated imine resveratrol analogues in the gas‐phase were investigated by electrospray ionization–tandem mass spectrometry. Benzyl cations were formed in the imine resveratrol analogues that had an ortho‐hydroxyl group on the benzene ring A. The specific elimination of the quinomethane neutral, CH₂ = C₆H₄ = O, from the two isomeric ions [M1 + H]⁺ and [M3 + H]⁺ via the corresponding ion–neutral complexes was observed. The fragmentation pathway for the related meta‐isomer, ion [M2 + H]⁺ and the other congeners was not observed. Accurate mass measurements and additional experiments carried out with a chlorinated analogue and the trideuterated isotopolog of M1 supported the overall interpretation of the fragmentation phenomena observed. It is very helpful for understanding the intriguing roles of ortho‐hydroxyl effect and ion–neutral complexes in fragmentation reactions and enriching the knowledge of the gas‐phase chemistry of the benzyl cation. Copyright © 2016 John Wiley & Sons, Ltd.     

Substituent effects on ultrafast excited-state proton transfer of protonated aniline derivatives in aqueous solution

Substituent effects on the proton dissociation of protonated aniline derivatives upon femtosecond laser pulse excitation are investigated for m- and p-cyanoanilines and m- and p-methoxyanilines in aqueous solution. The cyano substitution at the meta-position increases the rate significantly (k_dis=3.7 × 10¹¹ s⁻¹) compared to aniline (k_dis=1.3 × 10¹⁰ s⁻¹), while the methoxy substitution reduces the rate remarkably. Either substituent at the para-position shows only slight influences on the rate. The strong dependences of the k_dis value on the substituent and the substituted position are reasonably explained on the basis of the free energy change.     

State-resolved infrared spectrum of the protonated water dimer: revisiting the characteristic proton transfer doublet peak

The infrared (IR) spectra of protonated water clusters encode precise information on the dynamics and structure of the hydrated proton. However, the strong anharmonic coupling and quantum effects of these elusive species remain puzzling up to the present day. Here, we report unequivocal evidence that the interplay between the proton transfer and the water wagging motions in the protonated water dimer (Zundel ion) giving rise to the characteristic doublet peak is both more complex and more sensitive to subtle energetic changes than previously thought. In particular, hitherto overlooked low-intensity satellite peaks in the experimental spectrum are now unveiled and mechanistically assigned. Our findings rely on the comparison of IR spectra obtained using two highly accurate potential energy surfaces in conjunction with highly accurate state-resolved quantum simulations. We demonstrate that these high-accuracy simulations are important for providing definite assignments of the complex IR signals of fluxional molecules.

We reveal the intricate dynamics of the proton shuttling motion in the Zundel ion by computing 900 high-accuracy vibrational eigenstates. We show how very subtle energetic changes in the vibrational modes lead to vastly different infrared spectra.     

The unimolecular chemistry of protonated glycine and the proton affinity of glycine: a computational model

The potential energy hypersurface of protonated glycine, GH⁺, has been investigated. The calculated G2(MP2) value for the proton affinity (PA) of glycine, PA _calc=895kJ mol⁻¹, is in good agreement with the experimental value which has been estimated to lie in the range 864kJ mol⁻¹ < PA _exp <891kJ mol⁻¹. Ab initio quantum chemical calculations of relevant parts of the potential energy surface of GH⁺ give a reaction model which is consistent with the observed mass spectrometric fragmentation pattern. The lowest energy unimolecular reactions of GH⁺ are two distinct processes: (1) loss of CO, which has a substantial barrier for the reverse reaction, and (2) loss of CO plus H₂O, which has no barrier for the reverse reaction. Received: 15 November 1996 / Accepted: 6 May 1997