Hans-Jörg Hofmann

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.

Proteolytically stable peptides by incorporation of α-Tfm amino acids

A series of model peptides containing α‐trifluoromethyl‐substituted amino acids in five different positions relative to the predominant cleavage site of the serine protease α‐chymotrypsin was synthesized by solution methods to investigate the influence of α‐Tfm substitution on the proteolytic stability of peptides. Proteolysis studies demonstrated absolute stability of peptides substituted in the P1 position and still considerable proteolytic stability for peptides substituted at the P2 and P′2 positions compared with the corresponding unsubstituted model peptide. Comparison with peptides containing the fluorine‐free disubstituted amino acid α‐aminoisobutyric acid allowed to separate electronic from steric effects. Furthermore, the absolute configuration of the α‐Tfm‐substituted amino acid was found to exert considerable effects on the proteolytic stability, especially in P′1 substituted peptides. Investigations of this phenomenon using empirical force field calculations revealed that in the (S,R,S)‐diasteromer the steric constraints exhibited by the α‐Tfm group can be outweighed by an advantageous interaction of the fluorine atoms with the serine side chain of the enzyme. In contrast, a favourable interaction between substrate and enzyme is impossible for the (S,S,S)‐diastereomer.

Artificial Chemokines: Combining Chemistry and Molecular Biology for the Elucidation of Interleukin-8 Functionality

How can we understand the contribution of individual parts or segments to complex structures? A typical strategy to answer this question is simulation of a segmental replacement followed by realization and investigation of the resulting effect in structure-activity studies. For proteins, this problem is commonly addressed by site-directed mutagenesis. A more general approach represents the exchange of whole secondary structure elements by rationally designed segments. For a demonstration of this possibility we identified the alpha-helix at the C-terminus of human interleukin-8 (hIL-8). Since this chemokine possesses four conserved cysteine residues, it can easily be altered by ligation strategies. A set of different segments, which are able to form amphiphilic helices, was synthesized to mimic the C-terminal alpha-helix. Beside sequences of alpha-amino acids, oligomers of non-natural beta(3)-amino acids with the side chains of canonical amino acids were introduced. Such beta-peptides form helices, which differ from the alpha-helix in handedness and dipole orientation. Variants of the semisynthetic hIL-8 proteins demonstrated clearly that the exact side chain orientation is of more importance than helix handedness and dipole orientation. The activity of a chimeric protein with a beta-peptide helix that mimics the side chain orientation of the native alpha-helix most perfectly is comparable to that of the native hIL-8. Concepts like this could be a first step toward the synthesis of proteins consisting of large artificial secondary structure elements.

Helices in peptoids of α- and β-peptides

Peptoids of α- and β-peptides (α- and β-peptoids) can be obtained by shifting the amino acid side chains from the backbone carbon atoms of the monomer constituents to the peptide nitrogen atoms. They are, therefore, N-substituted poly-glycines and poly-β-alanines, respectively. Due to the substituted nitrogen atoms, the ability for hydrogen bond formation between peptide bonds gets lost. It may be very interesting to see whether such non-natural oligomers could be regarded as foldamers, which fold into definite backbone conformers. In this paper, we provide a complete overview on helix formation in α- and β-peptoids on the basis of systematic theoretical conformational analyses employing the methods of ab initio molecular orbital (MO) theory. It can be shown that the α- and β-peptoid structures form helical structures with both trans and cis peptide bonds despite the missing hydrogen bonds. Obviously, the conformational properties of the backbone are more important for folding than the possibility of hydrogen bonding. There are close relationships between the helices of α-peptoids and poly-glycine and poly-proline helices of α-peptides, whereas the helices of β-peptoids correspond to the well-known helical structures of β-peptides as, for instance, the 31-helix of β-peptides with 14-membered hydrogen-bonded rings. Thus, α- and β-peptoids enrich the field of foldamers and may be used as useful tools in peptide and protein design.

Problems concerning the theoretical treatment of tautomeric equilibria of hetrocycles

Abstract Quantum chemical calculations on four typical lactam-lactim tautomeric pairs of heterocycles have been performed using the CNDO/2, NDDO, MINDO/2, MINDO/3, MNDO, and STO-3G methods. In all cases, the hydroxy form is strongly favoured. Relative to the graduation of the total energy differences of the various equilibria, only the MNDO and STO-3G methods provide a qualitatively correct sequence. Calculations of the zero-point vibration energies, of the entropies, and of the temperature dependence of the enthalpies for the isomers indicate that a statistical-thermodynamic treatment may be omitted for such equilibria in most cases.

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

Conformational properties of azapeptides

The conformation of several model compounds for azapeptides was systematically examined on the basis of ab initio MO theory at various approximation levels. The calculations show the azapeptide conformation essentially determined by the hydrazine and urea constituents along the sequence. This leads to a characteristic conformer pattern which excludes the possibility of β sheet conformations, but indicates a high potency for the formation of helix and β turn structures. The Nα atom may change between planar and pyramid structures. The peculiar conformation properties make azaamino acids an attractive tool for secondary structure design in peptides and proteins.

Quantum chemical calculations for the determination of the molecular structure of conjugated compounds: Part XIV. On the conformational structure of α-diimine ligands

Abstract The conformational structure of some typical α-diimine ligands (2,2′-bipyridyl, glyoxaldiimine, glyoxal-N,N′-dimethyldiimine) is examined using the NDDO method. An analysis of the potential energy curves indicates the influence of specific lone-pair effects on the molecular structure. Based on a continuum model, changes of the molecular arrangement caused by solvent effects are estimated.

Rotation and inversion states in thermal E/Z isomerization of aromatic azo compounds

Abstract Ab initio calculations in a variation—perturbation scheme have been carried out on the three molecules of diazene, phenyldiazene and azobenzene with a view to clarifying the Z/E isomerization mechanism. It is found that, contrary to the usual belief, the rotational isomerization mechanism shows an energy barrier quite comparable to the inversional one and cannot generally be discarded in the Z/E thermal conversion.

Synthesis and Structure of α/δ-Hybrid Peptides—Access to Novel Helix Patterns in Foldamers

Stimulated by an overview on all periodic folding patterns of alpha/delta-hybrid peptides with 1:1 alternating backbone provided by ab initio molecular orbital theory, the first representatives of this foldamer class were synthesized connecting novel C-linked carbo-delta-amino acid constituents and L-Ala. In agreement with theoretical predictions, extensive NMR spectroscopic analyses confirm the formation of new motifs of 13/11-mixed helical patterns in these peptides supported by the rigidity of the D-xylose side chain in the selected delta-amino acid constituents. Relationships between possible helix types in alpha/delta-hybrid peptides and their counterparts in other 1:1 hybrid peptide classes and native alpha-peptides are discussed; these indicate the high potential of these foldamers to mimic native peptide secondary structures. The design of alpha/delta-hybrid peptides provides an opportunity to expand the domain of foldamers and allows the introduction of desired functionalities through the alpha-amino acid constituents.