Kerstin Möhle

Basic conformers in β-peptides

The conformation of oligomers of beta-amino acids of the general type Ac-[beta-Xaa]n-NHMe (beta-Xaa = beta-Ala, beta-Aib, and beta-Abu; n = 1-4) was systematically examined at different levels of ab initio molecular orbital theory (HF/6-31G*, HF/3-21G). The solvent influence was considered employing two quantum-mechanical self-consistent reaction field models. The results show a wide variety of possibilities for the formation of characteristic elements of secondary structure in beta-peptides. Most of them can be derived from the monomer units of blocked beta-peptides with n = 1. The stability and geometries of the beta-peptide structures are considerably influenced by the side-chain positions, by the configurations at the C alpha- and C beta-atoms of the beta-amino acid constituents, and especially by environmental effects. Structure peculiarities of beta-peptides, in particular those of various helix alternatives, are discussed in relation to typical elements of secondary structure in alpha-peptides.

Structural and energetic relations between ? turns

A systematic quantum chemical study on the structure and stability of the major types of β‐turn structures in peptides and proteins was performed at different levels of ab initio MO theory (MP2/6‐31G*, HF/6‐31G*, HF/3‐21G) considering model turns of the general type Ac(SINGLE BOND)Xaa(SINGLE BOND)Yaa(SINGLE BOND)NHCH3 with the amino acids glycine, l‐ and d‐alanine, aminoisobutyric acid, and l‐proline. The influence of correlation effects, zero‐point vibration energies, thermal energies, and entropies on the turn formation was examined. Solvent effects on the turn stabilities were estimated employing quantum chemical continuum approaches (Onsagers self‐consistent reaction field and Tomasis polarizable continuum models). The results provide insight into the geometry and stability relations between the various β‐turn subtypes. They show some characteristic deviations from the widely accepted standard rotation angles of β turns. The stability order of the β‐turn subtypes depends strongly on the amino acid type. Thus, the replacement of l‐amino acids in the two conformation‐determining turn positions by d‐ or α,α‐disubstituted amino acid residues generally increases the turn formation tendency and can be used to favor distinct β‐turn subtypes in peptide and protein design. The β‐turn subtype preferences, depending on amino acid structure modifications, can be well illustrated by molecular dynamics simulations in the gas phase and in aqueous solution. © 1997 by John Wiley & Sons, Inc. J Comput Chem 18: 1415–1430, 1997

Description of peptide and protein secondary structures employing semiempirical methods

Novel semiempirical methods (OM1, OM2) have been employed to study typical elements of secondary structure in peptides and proteins. The calculated geometries and relative stabilities are discussed in comparison to corresponding data from the ab initio MO theory and from the established semiempirical methods AM1 and PM3, respectively. It is shown that the description of the peptide conformers is considerably improved by OM1 and OM2 compared with AM1 and PM3, although in some cases there are still discrepancies with the ab initio data.

Molecular dynamics study of hyaluronic acid in water

Abstract Molecular dynamics (MD) simulations on hyaluronic acid (HA)-water systems were carried out to study the HA-water interactions. Employing the GROMOS force field and the SPC water model, HA dimer and trimer subunits surrounded by 490 water molecules were investigated. For each system pair distribution functions, diffusion coefficients and reorientation correlation times of the water molecules were calculated from 450 ps trajectories. The average values of the interglycosidic angles found in the simulations are φ 13 = 52 °, ψ 13 = 25 ° for the β(1,3) linkage, and φ 14 = 40 °, ψ 14 = 3 ° for the β(1,4) linkage well corresponding to the minimum regions in Ramachandran plots. The self-diffusion coefficients of the water molecules vary from 1.5 × 10 −9 m 2 s −1 to 2.3 × 10 −9 m 2 s −1 dependent on the distance between the water molecules and the atoms of the HA molecule. The reorientation correlation times of the water molecules were estimated to be about 2 ps at a polymer concentration of 7 wt.% HA. On the basis of energy and geometry criteria, the number of hydrogen bonds between the water molecules and the acceptor atoms of HA was determined to be between 10 and 15 per dimer unit indicating the high hydration ability of hyaluronic acid in comparison to other di- and oligosaccharides.

Molecular dynamics of a tetrasaccharide subunit of chondroitin 4-sulfate in water.

Molecular dynamics (MD) simulations on a tetrasaccharide subunit of chondroitin 4-sulfate (CS4) in aqueous solution were carried out to study its interactions with water. Pair distribution functions and diffusion coefficients were calculated from a 4 ns trajectory and the hydration of different molecular groups was analysed. The average values of the interglycosidic torsion angles found in the simulations are phi 13 = -10 degrees, psi 13 = -85 degrees and phi 13 = 80 degrees, psi 13 = 90 degrees for the beta-(1-->3) linkage, and phi 14 = -10 degrees, psi 14 = -70 degrees for the beta-(1-->4) linkage. Hydrophobic patches formed by sugar ring CH groups were found. The diffusion coefficients of the water molecules vary from 1.4 x 10(-9) to 2.3 x 10(-9) m2 s-1 depending on the distances between the water molecules and the atoms of the CS4 molecule and the type of CS4 atoms, respectively. Reorientation correlation times of the water molecules in the vicinity of different CS4 atoms were estimated to be about 1 ps at a polymer concentration of 4 wt.% CS4. The number of hydrogen bonds between the water molecules and the acceptor atoms of CS4 was determined to be about 20 per disaccharide unit, indicating a higher hydration ability of chondroitin sulfate in comparison with non-sulfated oligosaccharides. Substructures, where water molecules are involved in hydrogen bonds to different sugar rings, were found, which may be important for the stabilisation of the secondary structure of the CS4 molecule.

Total synthesis of the peptaibols hypomurocin A3 and hypomurocin A5, and their conformation analysis.

The total syntheses of hypomurocin A3 and hypomuricin A5 (HM A3 and HM A5, resp.) in solution phase are described. These syntheses have been successfully achieved by applying the ‘azirine/oxazolone method’ to introduce the two Aib‐Pro units into the backbone of these undecapeptaibols in one step with methyl 2,2‐dimethyl‐2H‐azirine‐3‐prolinate as the ‘Aib‐Pro synthon’. The coupling of Z‐protected (Z=(benzyloxy)carbonyl) amino acids or peptide acids with amino acid tert‐butyl esters and of peptide segments was carried out according to the TBTU (=O‐(benzotriazol‐1‐yl)‐N,N,N′,N′‐tetramethyluronium tetrafluoroborate) and HOBt (=1‐hydroxybenzotriazole) protocol. Purification by reversed‐phase HPLC gave the peptides in pure form. The products were characterized by optical rotation, NMR and IR spectroscopy, mass spectrometry, and elemental analysis. The crystal structures of HM A3 and of an octapeptide fragment of HM A5 could be obtained. An NMR analysis was also carried out with HM A3 and HM A5 to determine their conformations in solution. A global structural comparison between the three sequences of HM A1, HM A3, and HM A5 was performed, as well as the HPLC correlation of the natural HM A family and the synthetic samples.

Conformational studies on peptides with unusual amino acid side-chains: The trifluoromethyl group

Abstract High-level ab initio MO calculations on the model compound N-acetyl-2-rifluoromethylglycyl-N′-methylamide as a basic peptide unit for an amino acid with a trifluoromethyl side-chain employing the 6-31G ∗ and 3-21G basis sets and considering the correlation energy by the MP2 method were performed. The influence of the trifluoromethyl group on the conformation possibilities of this structure element was determinated in comparison with the corresponding alanine and valine derivatives in the gas phase and in solution. The conformers were characterized by vibration analysis. The solvent influence was estimated using a polarizable continuum model incorporated into the ab initio procedure. The conformation dynamics in the various states of matter was studied by molecular dynamics simulations based on the empirical GROMOS force field. Most striking is the preference of the C 5 conformation over the C 7 eq form contrary to the corresponding alanine and valine derivative. Thus, a stronger tendency to form β-structures can be expected for amino acids with a trifluoromethyl side-chain. Again in contrast to the alanine derivative, the helical α R conformation is not realized in solution.