Studying the Stability of a Helical β-Heptapeptide by Molecular Dynamics Simulations

β‐Peptides consisting entirely of homochiral β‐amino acids R‐CH(NH2)‐CH2CO2H form 31‐helices in solution, as shown previously by NMR analysis of pyridine and methanol solutions. The stability of the helical secondary structure of one such β‐peptide (H‐β‐HVal‐β‐HAla‐β‐HLeu‐(S,S)‐β‐HAla(αMe)‐β‐HVal‐β‐HAla‐β‐HLeu‐OH, 1) has been investigated by molecular dynamics simulations using the GROMOS 96 molecular model and force field (962 methanol molecules; T = 298, 350, 400 K; with and without NOE distance restraints). The restraints derived from the NMR studies were equally well satisfied by both the restrained and the unrestrained room‐temperature molecular dynamics simulations. The 31‐helical conformation of 1 was shown to be so stable that it was restored spontaneously within 400 ps after unfolding had been induced by a sudden increase of the temperature from 298 to 350 K. Considerable efforts are being invested into designing synthetic molecules that fold into well‐defined three‐dimensional structures. These may be based on previously known or less familiar motifs. Thus, α‐amino acids are not the only amino‐acid building blocks that can be used to design molecular chains with stable folds. We have used molecular dynamics simulations to study the stability of the 31‐ (left‐handed) helix adopted by a synthetic β‐heptapeptide (composed of β‐amino acid residues; see Figure) in methanol solution.