Amide Cis ‐ Trans Isomerization in Peptides and Proteins

Abstract

Imidic and secondary amide peptide bonds, echoing motifs of the backbone of oligopeptides and proteins, are among the most widespread functional groups of bioactive molecules. Nineteen out of the 20 gene-coded amino acids form secondary amide peptide bonds, whereas the peptide bond preceding proline is imidic in its chemical nature. Planarity and strong conformational preferences are general features of peptide bonds. Nevertheless, slight deviation from planarity is common in folded polypeptide chains [1][2][3]. The cis-trans isomers of simple secondary and substituted tertiary amides, such as N-methyl acetamide and N,N-dimethyl acetamide respectively, because of the predictive capability of their molecular parameters, have often been used for the analysis of thermodynamics and kinetics of cis-trans isomerization (CTI) in polypeptide chains. This field is covered by many reviews [4][5][6][7][8]. Thus, restrictions in the number of energy minima in peptide bond torsion (dihedral angle x) as well as in the ease in surmounting the energy barrier separating the isomers is in keeping with the classic view of amide bond resonance, and is best illustrated by assuming a partial double bond character of the C-N bond of the peptide unit ( Fig. 9.1) [9]. For simple amides, geometric isomers with the angle x » 0 (cis) and x » 180 (trans) coexist in solution as demonstrated in the mid 1950s, together with the slow C-N bond rotation by 1 H NMR spectroscopy for dimethyl formamide. The barriers of rotation can be calculated from the rate constants of CTI yielding DG ‡ values for N-methyl acetamide of 79 kJ mol -1 for the cis to trans transition and DG ‡ = 89 kJ mol -1 for the reverse reaction (30 C, water) [10]. Detailed knowledge on the thermodynamic origin of CTI remains nonetheless limited, and predictions of ratios of isomers and barrier heights across different chemical structures are difficult. In the transition state of peptide bond rotation, twisted C (carbonyl) as well as N pyramidal configurations cis-trans Isomerization in Biochemistry. Edited by Christophe Dugave have to be considered. Indeed, ground-state nonplanarity causes reduction of the rotational barriers in a series of constrained amides [11].Clearly, CTI leads to a periodic backbone contraction/expansion of the polypeptide chain involved, as could be inferred from the isomer-specific distances of the C a atoms directly attached to the isomerizing peptide bond. For prolyl bonds in native proteins this distance is about 0.8 shorter in the cis isomer when compared to the respective trans isomer [12]. This atomic translation produces a mechanical moment that was hypothesized to be involved in the functional cycle of motor proteins [13].Provided that stabilizing tertiary interactions or steric constraints are absent in the respective molecules, secondary amides show a preference for the trans isomer in solution. It is obvious that the cis form is energetically less stable due to steric repulsion of the neighboring C a atoms. The steric advantage of the trans conf...

Amide Cis−Trans Isomerization in Aqueous Solutions of Methyl N-Formyl-d-glucosaminides and Methyl N-Acetyl-d-glucosaminides: Chemical Equilibria and Exchange Kinetics

“…Upon detection of signals attributable to a putative cis isomer based on chemical shift and J CC arguments, 13 C-labeling at either the side chain carbonyl carbon or the C2 ring carbon would then be exploited in quantitative 13 C saturation-transfer experiments to confirm the presence of cis ⇄ trans chemical exchange and allow measurements of first-order rate constants as a function of temperature, from which kinetics parameters could be determined. The magnitude of the latter values would provide indirect evidence for cis ⇄ trans equilibria in solution, since these parameters have been measured previously in related systems. ,, …”

3-Substituted Prolines: From Synthesis to Structural Applications, from Peptides to Foldamers

“…The use of cis -3-substituted prolinoamino acids in combination with N -methyl- or cyclopropyl amino acids has been reported to stabilize type II’ β-turns in water that retain the side-chain functionalities in both i+1 and i+2 positions of the turn [ 50 , 68 ]. These short peptides incorporate three motifs, a heterochiral sequence, a proline scaffold and a N -methyl group or a cyclopropylamino acid, that are known to exhibit strong β-turn propensity ( Figure 5 ) [ 1 , 73 , 74 , 75 ]. The prolinoamino acid allows to mimic the canonical staggered rotamers of the side chains in i+1 position with minimal deviation and its combination with N -methyl- or cyclopropylamino acids allows one to mimic the three canonical rotamers of the χ1 angle in position i+2 of the turn.…”

“…Among the twenty natural amino acids, proline is unique as its secondary amine forms a tertiary amide when incorporated into biopolymers, thus preventing hydrogen bond formation. Regarding the conformational space around proline residues, if the pyrrolidine ring restricts the flexibility of Φ and ψ peptide backbone dihedral angles, at the same time the formed tertiary amide bond is more susceptible to cis / trans isomerism extending the accessible conformational space around the ω dihedral angle [ 1 ] Despite the lack of hydrogen bond donor capability, proline is able to stabilize peptide secondary structures such as turns [ 2 ] or helices (PPI and PPII helices) [ 3 , 4 ]. These unique conformational properties of proline have aroused a great interest leading to the development of many analogues ( Figure 1 ) useful for peptide syntheses, SAR studies, design of bioactive peptides or secondary structures mimics [ 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 ].…”

Diastereoselective Synthesis of 5-Heteroaryl-Substituted Prolines Useful for Controlling Peptide-Bond Geometry

“…Conformationally rigid peptides often are preferred over small molecule based therapeutics as they alleviate the drawbacks caused by the latter. For designing peptide-based therapeutics, proline was often a preferred choice, as it brings conformationally rigidity . Furthermore, proline and its derivatives have been extensively used as organocatalysts in stereoselective reactions .…”