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

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.