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

The conformational tendencies of Calpha,alpha-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-alpha-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 3(10)-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 alpha-carbon symmetry of achiral C-alpha-tetrasubstituted amino acids is a promising strategy to build up polypeptides with modulated conformational tendencies.