Imre G. Csizmadia

WHY ARE B IONS STABLE SPECIES IN PEPTIDE SPECTRA

Protonated amino acids and derivatives RCH(NH2)C(+O)X · H+ (X = OH, NH2, OCH3) do not form stable acylium ions on loss of HX, but rather the acylium ion eliminates CO to form the immonium ion RCH = NH2+. By contrast, protonated dipeptide derivatives H2NCH(R)C(+O)NHCH(R′)C(+O)X · H+ [X = OH, OCH3, NH2, NHCH(R″)COOH] form stable B2 ions by elimination of HX. These B2 ions fragment on the metastable ion time scale by elimination of CO with substantial kinetic energy release (T1/2 = 0.3–0.5 eV). Similarly, protonated N-acetyl amino acid derivatives CH3C(+O)NHCH(R′)C(+O)X · H+ [X = OH, OCH3, NH2, NHCH(R″)COOH] form stable B ions by loss of HX. These B ions also fragment unimolecularly by loss of CO with T1/2 values of ∼ 0.5 eV. These large kinetic energy releases indicate that a stable configuration of the B ions fragments by way of activation to a reacting configuration that is higher in energy than the products, and some of the fragmentation exothermicity of the final step is partitioned into kinetic energy of the separating fragments. We conclude that the stable configuration is a protonated oxazolone, which is formed by interaction of the developing charge (as HX is lost) with the N-terminus carbonyl group and that the reacting configuration is the acyclic acylium ion. This conclusion is supported by the similar fragmentation behavior of protonated 2-phenyl-5-oxazolone and the B ion derived by loss of H-Gly-OH from protonated C6H5C(+O)-Gly-Gly-OH. In addition, ab initio calculations on the simplest B ion, nominally HC(+O)NHCH2CO+, show that the lowest energy structure is the protonated oxazolone. The acyclic acylium isomer is 1.49 eV higher in energy than the protonated oxazolone and 0.88 eV higher in energy than the fragmentation products, HC(+O)N+H = CH2 + CO, which is consistent with the kinetic energy releases measured.

The structure and fragmentation of Bn (n ≥ 3) ions in peptide spectra

The unimolecular and low energy collision-induced fragmentation reactions of the MH+ ions of N-acetyl-tri-alanine, N-acetyl-tri-alanine methyl ester, N-acetyl-tetra-alanine, tetra-alanine, penta-alanine, hexa-glycine, and Leu-enkephalin have been studied with a particular emphasis on the formation and fragmentation of Bn (n=3,4,5) ions. In addition, the metastable ion fragmentation reactions of protonated tetra-glycine, penta-glycine, and Leu-enkephalin amide have been studied. Bn ions are prominent stable species in all spectra. The Bn ions fragment, in part, by elimination of CO to form An ions; this reaction occurs on the metastable ion time scale with a substantial release of kinetic energy (T1/2=0. 3–0. 5 eV) that indicates that a stable configuration of the Bn ion fragments by way of a reacting configuration that is higher in energy than the fragmentation products, An + CO. Ab initio calculations strongly suggest that the stable configuration of the B3 and B4 ions is a protonated oxazolone formed by interaction of the developing charge with the next-nearest carbonyl group as HX is lost from the protonated species H-(Yyy)n-X · H+. The higher Bn ions also fragment, in part, to form the next-lower B ion, presumably in its stable protonated oxazolone form. This reaction is rationalized in terms of the three-dimensional structure of the Bn ions and it is proposed that the neutral eliminated is an α-lactam.

New theoretical concepts for understanding organic reactions

Multidimensional theoretical stereochemistry and conformational potential energy surface topology.- Some practical suggestions for optimizing geometries and locating transition states.- Reaction topology and quantum chemical molecular design on potential energy surfaces.- Topology of molecular shape and chirality.- Adiabatic and diabatic surfaces in the treatment of chemical reactivity. I. Theory.- Adiabatic and diabatic surfaces in the treatment of chemical reactivity. II. An illustrative application to the Diels Alder reaction.- A qualitative valence bond model for organic reactions.- Solvent effects on potential energy surfaces and chemical kinetics.- Modifications of potential energy surfaces by solvation and catalysis.- Computational tests of potential energy surfaces from dynamical properties.- Dynamical formulation of transition state theory: variational transition states and semiclassical tunneling.- Theoretical models for reaction dynamics in polyatomic molecular systems.- Practical applications of new theoretical concepts in organic chemistry.

Ab Initio SCF–MO–CI Calculations for H−, H2, and H3+ Using Gaussian Basis Sets

Fixed‐center Gaussian‐type functions (GTF) have been used as basis sets in an extensive SCF–MO–CI study on H−, H2, and H3+. An accurate description requires 4 or 5 s‐GTF on each center, plus at least one set of p‐GTF, which are essential for the reproduction of reliable potential curves; d‐GTF are, however, of minor importance. A constant p exponent may be used successfully in a wide variety of nuclear configurations. Variational energies of − 1.3397 and − 1.2765 hartree were calculated for the most stable equilateral and collinear geometries of H3+. A potential‐energy surface has been computed for the reaction H+ + H2, to an accuracy of about 2 kcal mole−1 over its important regions. In the computation of the proton affinites of H− and H2, little accuracy was lost when a limited basis set was used in SCF calculations.

Theoretical and Computational Models for Organic Chemistry

Proceedings of the NATO ASI held in Praia de Porto Novo, Portugal, August/September 1990. Ranges over the realm of theoretical and physical organic chemistry, from a novel potential energy surface for O 4, relevant for the processes occurring in the ozone layer, to models of the three-dimensional st

Theoretical Study on the Proton Affinity of Small Molecules Using Gaussian Basis Sets in the LCAO–MO–SCF Framework

The proton affinities of certain small molecules have been calculated as an energy difference between the parent molecule and the protonated species. Various size Gaussian basis sets were used to see how the calculated proton affinities approximate the experimental values as the wavefunctions approached the Hartree–Fock limit. The correlation between experimental and calculated proton affinities was excellent with the extensive basis sets.

Structure and fragmentation of b2 ions in peptide mass spectra

In a number of cases the b2 ion observed in peptide mass spectra fragments directly to the a1 ion. The present study examines the scope of this reaction and provides evidence as to the structure(s) of the b2 ions undergoing fragmentation to the a1 ion. The b2 ion H-Ala-Gly+ fragments, in part, to the a1 ion, whereas the isomeric b2 ion H-Gly-Ala+ does not fragment to the a1 ion. Ab initio calculations of ion energies show that this different behavior can be rationalized in terms of protonated oxazolone structures for the b2 ions provided one assumes a reverse activation energy of ∼1 eV for the reaction b2 → a2; such a reverse activation energy is consistent with experimental kinetic energy release measurements. Experimentally, the H-Aib-Ala+ b2 ion, which must have a protonated oxazolone structure, fragments extensively to the a1 ion. We conclude that the proposal by Eckart et al. (J. Am. Soc. Mass Spectrom. 1998, 9, 1002) that the b2 ions which undergo fragmentation to a1 ions have an immonium ion structure is not necessary to rationalize the results, but that the fragmentation does occur from a protonated oxazolone structure. It is shown that the b2 → a1 reaction occurs extensively when the C-terminus residue in the b2 ion is Gly and with less facility when the C-terminus residue is Ala. When the C-terminus residue is Val or larger, the b2 → a1 reaction cannot compete with the b2 → a2 fragmentation reaction. Some preliminary results on the fragmentation of a2 ions are reported.

In Silico Study of Full-Length Amyloid β 1−42 Tri- and Penta-Oligomers in Solution

Amyloid oligomers are considered to play causal roles in the pathogenesis of amyloid-related degenerative diseases including Alzheimers disease. Using MD simulation techniques, we explored the contributions of the different structural elements of trimeric and pentameric full-length Abeta1-42 aggregates in solution to their stability and conformational dynamics. We found that our models are stable at a temperature of 310 K, and converge toward an interdigitated side-chain packing for intermolecular contacts within the two beta-sheet regions of the aggregates: beta1 (residues 18-26) and beta2 (residues 31-42). MD simulations reveal that the beta-strand twist is a characteristic element of Abeta-aggregates, permitting a compact, interdigitated packing of side chains from neighboring beta-sheets. The beta2 portion formed a tightly organized beta-helix, whereas the beta1 portion did not show such a firm structural organization, although it maintained its beta-sheet conformation. Our simulations indicate that the hydrophobic core comprising the beta2 portion of the aggregate is a crucial stabilizing element in the Abeta aggregation process. On the basis of these structure-stability findings, the beta2 portion emerges as an optimal target for further antiamyloid drug design.

Relative stability of 1C4 and 4C1 chair forms of β-d-glucose: a density functional study

Abstract The method and basis set dependence of the relative energies of the 1 C 4 and 4 C 1 chair forms of β- d -glucose were calculated for two selected, low-energy hydroxyl rotamers at various levels of generalized gradient approximation density functional theory (GGA-DFT). The GGA-DFT and MP2 methods provide similar energetic differences for β- d -glucose conformers. Addition of the diffuse functions to a double-zeta quality basis set and inclusion of the HF exchange into the DFT functionals improve the agreement between the DFT and the best composite estimates of the energetic differences. The GGA- or hybrid-DFT methods reproduce the geometrical consequences of correlation effects correctly for glucose.

Peptide models. XXXIII. Extrapolation of low-level Hartree-Fock data of peptide conformation to large basis set SCF, MP2, DFT, and CCSD(T) results. The Ramachandran surface of alanine dipeptide computed at various levels of theory

At the dawn of the new millenium, new concepts are required for a more profound understanding of protein structures. Together with NMR and X‐ray‐based 3D‐stucture determinations in silico methods are now widely accepted. Homology‐based modeling studies, molecular dynamics methods, and quantum mechanical approaches are more commonly used. Despite the steady and exponential increase in computational power, high level ab initio methods will not be in common use for studying the structure and dynamics of large peptides and proteins in the near future. We are presenting here a novel approach, in which low‐ and medium‐level ab initio energy results are scaled, thus extrapolating to a higher level of information. This scaling is of special significance, because we observed previously on molecular properties such as energy, chemical shielding data, etc., determined at a higher theoretical level, do correlate better with experimental data, than those originating from lower theoretical treatments. The Ramachandran surface of an alanine dipeptide now determined at six different levels of theory [RHF and B3LYP 3‐21G, 6‐31+G(d) and 6‐311++G(d,p)] serves as a suitable test. Minima, first‐order critical points and partially optimized structures, determined at different levels of theory (SCF, DFT), were completed with high level energy calculations such as MP2, MP4D, and CCSD(T). For the first time three different CCSD(T) sets of energies were determined for all stable B3LYP/6‐311++G(d,p) minima of an alanine dipeptide. From the simplest ab initio data (e.g., RHF/3‐21G) to more complex results [CCSD(T)/6‐311+G(d,p)//B3LYP/6‐311++G(d,p)] all data sets were compared, analyzed in a comprehensive manner, and evaluated by means of statistics.