Computer simulation of the conformational properties of retro–inverso peptides. I. Empirical force field calculations of rigid and flexible geometries of N‐acetylglycine‐N′‐ methylamide, bis(acetamido) methane, and N, N′‐ dimethylmalonamide and their corresponding Cα‐methylated analogs

Rigid and flexible geometry calculations are described for N ‐acetylglycine‐ N ′‐methylamide, N ‐acetylalanine‐ N ′‐methylamide, and their retro‐inverso analogs, bis(acetamido) methane, 1,1‐bis(acetamido) ethane, N , N ′‐dimethylmalonamide, and N , N ′‐dimethyl‐2‐methyl‐malonamide. The significance of relaxing all degrees of freedom, especially angular flexibility is demonstrated. The flexible geometry approach yields energy maps similar to those from rigid geometry, but the energy barriers between minima are substantially reduced, leading in general, to more probable transitions and a higher volume of accessible conformational space. Whereas the glycine and alanine derivatives exhibit their lowest energy minima in the C region, the gem ‐diaminoalkyl and malonyl residues show their lowest minima in the “α‐helical” regions. With respect to the effect of side chains (H versus CH 3 ), the greatest conformational influence appears with the gem ‐diaminoalkyl residues. These results indicate significantly different conformational behavior of retro peptides and the implications of these pairwise incorporations of retro‐inverso residues in peptide chains, are discussed.