The conformational preferences of ?-lactam and its role in constraining peptide structure

Abstract

The conformational constraints imposed by gamma-lactams in peptides have been studied using valence force field energy calculations and flexible geometry maps. It has been found that while cyclisation restrains the psi of the lactam, non-bonded interactions contribute to the constraints on psi of the lactam. The gamma-lactam also affects the (psi, psi) of the residue after it in a peptide sequence. For an L-lactam, the ring geometry restricts psi to about -120 degrees, and psi has two minima, the lowest energy around -140 degrees and a higher minimum (5 kcal/mol higher) at 60 degrees, making an L-gamma-lactam more favourably accommodated in a near extended conformation than in position 2 of a type II' beta-turn. The energy of the psi approximately +60 degrees minimum can be lowered substantially until it is more favoured than the -140 degrees minimum by progressive substitution of bulkier groups on the amide N of the L-gamma-lactam. The (psi, psi) maps of the residue succeeding a gamma-lactam show subtle differences from those of standard N-methylated residues. The dependence of the constraints on the chirality of gamma-lactams and N-substituted gamma-lactams, in terms of the formation of secondary structures like beta-turns is discussed and the comparison of the theoretical conformations with experimental results is highlighted.

Stereo- and Regiochemical Transannular Cyclization of a Common Hexahydro-1H-azonine to Afford Three Different Indolizidinone Dipeptide Mimetics

“…The double bond character of the central amide flattens the ring system and causes a pseudo-A­(1,3) strain that positions the proline or pipecolate carboxylate in a pseudoaxial orientation, which is more favored in the case of the latter I 9 aa systems . In the case of the parent five-membered lactam, the ψ values have been respectively shown by computation to be −120° and the X-ray crystallography to be −115° . Substituents at the ring positions of I 2 aa, I 9 aa, and thiaindolizidinone counterparts may significantly influence ϕ i +2 and ψ i +1 dihedral angels.…”

Pyridone Dipeptides – Synthesis of a Novel Peptide Chromophore

“…[3] Smaller lactam rings (n = 0, 1) are flattened and minima of -140°or 60°a re expected for φ 1 . [4] The pyridone dipeptide 1 combines an NH donor and CO acceptor of parallel orientation (φ 1 = 180°) and a thiaproline ring which induces a close to right angle in the peptide structure (φ 2 = -60°to -90°). The synthetic strategy presented here extends our earlier approach towards bicyclic thiazolidine lactams.…”