DFT studies on helix formation in N-acetyl-(L-alanyl)n-N′-methylamide for n=1–20 Original Research Article

We compare the geometries and relative energies of important secondary structural elements, the 3.613 helix, 310 helix and C5ext structures, for a set of blocked peptide models, N-acetyl-(L-alanyl)n-N′-methylamide, for n=1–20. We use full density-functional theory (DFT) calculations at the B3LYP/6-31G* level (for peptides up to 11 residues), the self-consistent-charge density-functional tight binding (SCC-DFTB) and the semiempirical AM1 method. The 3.613 and 310 structures are found to be not inherently stable in general. Their stability is dependent on peptide length, other structural motifs and aqueous or membrane environments. For short peptides with less than eight residues, the 3.613 helix relaxes into the 310 structure. For longer peptides, the 3.613 is stable in the middle of the chain, while the ends assume 310 conformations, at the C-terminus additionally a βII type turn is formed. The relative energies and structures calculated with the recently developed SCC-DFTB method are in very good agreement with the results from the B3LYP density-functional calculations. Therefore, we use the SCC-DFTB method to look at helix formation in N-acetyl-(L-alanyl)n-N′-methylamide for n=11, 14, 17 and 20. On the SCC-DFTB potential energy surface, we find the 310 helix to be more stable than the 3.613 helix for all peptide sizes. However, the effects of solution might change this picture and favor the 3.613 motif.