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

The conformational tendencies of C α,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 ‐O t Bu (Tfa, trifluoroacetyl; O t Bu, 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 ‐O t Bu, Tfa‐(Deg) 2 ‐ L ‐Abu‐(Deg) 2 ‐O t Bu, Tfa‐(Deg) 3 ‐ L ‐Abu‐Deg‐O t Bu, and Tfa‐(Deg) 4 ‐ L ‐Abu‐O t Bu. Simulations show that only the Deg homopeptide is able to stabilize a 2.0 5 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 ‐O t Bu highlighted that, when the size of the Deg segments increases, their tendency to adopt a 2.0 5 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 C α ‐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. This article was originally published online as an accepted preprint. The “Published Online” date corresponds to the preprint version. You can request a copy of the preprint by emailing the Biopolymers editorial office at biopolymers@wiley.com