Conformational studies into N-methylation of alanine diamide models: A quantitative approach

A systematic theoretical analysis was performed on N-acetyl-l-alanine N′-methylamide (Ac-l-Ala-NHMe) and the analogues methylated on the N-terminus (Ac-l-(Me)Ala-NHMe), C-terminus (Ac-l-Ala-NMe2), and both N/C-termini (Ac-l-(Me)Ala-NMe2), to evaluate the influence of methylation of the amide group on the conformational properties of the affected residues. The ϕ, ψ potential energy surfaces were calculated at the B3LYP/6-31+G**//HF/3-21G level of theory with inclusion of the solvent (water) effect (SCRF method). The conformers localised were fully optimised at the B3LYP/6-31+G** in vacuo. The accessible areas of the potential energy surfaces; the number of conformers and the stabilising internal forces were compared for all the studied molecules. For comparison, data drawn from the Cambridge Crystallographic Data Centre has been presented. The conformational freedom of residue methylated either on the N-terminal (trans and cis) or C-terminal amide group is reduced, in contrast to residue methylated on both the N/C-terminal amide groups. For all the studied molecules the lowest energy conformers have the methylated amide bond in the trans configuration. NH⋯O hydrogen bonds stabilise the lowest conformers of Ac-l-Ala-NMe2 and all the conformers of trans-Ac-l-(Me)Ala-NHMe, but not those of cis-Ac-l-(Me)Ala-NHMe where NH⋯N operates. For all the methylated residues studied, the weaker CH⋯O hydrogen bonds and the carbonyl CO▶⋯◀CO attractions seem to play an important role.