Correlation between symmetry breaker position and the preferences of conformationally constrained homopeptides: a molecular dynamics investigation.
The conformational tendencies of C(alpha,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 2.0(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)-OtBu 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 alpha-carbon symmetry of achiral C(alpha)-tetrasubstituted amino acids is a promising strategy to build up polypeptides with modulated conformational tendencies.
Departament d'Enginyeria Química, EUETII, Universitat Politècnica de Catalunya, Pça Rei 15, Igualada 08700, Spain.
Juan
J
Torras
David
D
Zanuy
Marco
M
Crisma
Claudio
C
Toniolo
Oscar
O
Betran
Carlos
C
Alemán
D000595:Amino Acid Sequence; D000613:Aminobutyrates / Q000737:chemistry / Q000378:metabolism; D003198:Computer Simulation; D005998:Glycine / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism; D008958:Models, Molecular; D010087:Oxides / Q000737:chemistry / Q000378:metabolism; D010455:Peptides / Q000737:chemistry* / Q000378:metabolism*; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D013816:Thermodynamics
D000613:Aminobutyrates; D010087:Oxides; D010455:Peptides; C062694:alpha-amino-2-ethylbutanoic acid; C052893:tert-butoxy; C012223:alpha-aminobutyric acid; D005998:Glycine