Correlation between symmetry breaker position and the preferences of conformationally constrained homopeptides: A molecular dynamics investigation

The conformational tendencies of Cα,α‐diethylglycine (Deg)‐based peptides have been studied in solution using all atom molecular dynamics simulations. Specifically, the conformational effects of breaking the symmetry of the host Tfa‐(Deg)5‐OtBu (Tfa, trifluoroacetyl; OtBu, tert‐butoxy) pentapeptide with punctual replacements at different sequence positions of one Deg residue by its corresponding guest chiral analogue, L‐α‐aminobutyric acid (L‐Abu), have been examined by simulating the following peptides: Tfa‐(Deg)5‐OtBu, Tfa‐(Deg)2‐L‐Abu‐(Deg)2‐OtBu, Tfa‐(Deg)3‐L‐Abu‐Deg‐OtBu, and Tfa‐(Deg)4‐L‐Abu‐OtBu. Simulations show that only the Deg homopeptide is able to stabilize a 2.05 helix, even though a kinked arrangement with all the Deg residues adopting a fully‐extended conformation was found to be stable when the L‐Abu residue is introduced in the middle of the sequence. On the other hand, when the L‐Abu residue is closer to the C‐end of the sequence, the peptide chain prefers a partially folded 310‐helix. Additional simulations on Tfa‐(Deg)3‐L‐Abu‐(Deg)3‐OtBu highlighted that, when the size of the Deg segments increases, their tendency to adopt a 2.05 helix predominates over the preferred folded conformation of L‐Abu. The overall picture extracted after more than 300 ns of molecular dynamics simulation is that breaking the α‐carbon symmetry of achiral Cα‐tetrasubstituted amino acids is a promising strategy to build up polypeptides with modulated conformational tendencies. © 2008 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 90: 695–706, 2008.