Title: Is there a Beta-Peptide Equivalent of the Alpha-Helix?
Abstract: In organic chemistry, the concept of homologation describes the extension of a carbon chain by one methylene unit. The application of this concept to peptides gives rise to the class of β-peptides that feature an additional -CH2- unit in the monomer backbone. The study of such non-natural peptides offers insight into general folding mechanisms. The similarities to α-peptide structure combined with stability against proteases makes such foldamers promising scaffolds with possible applications in drug design. With regards to such applications it is remarkable that until now no β-peptide structure with the same H-bonding pattern as the α-helix was found. Hints for this structure stem from a previous theoretical study [1] and from diffraction experiments on Nylon-3 [2]. We compare the β-peptide Ac-β2hAla6-Lys(H+) to the α-peptide Ac-Ala6-Lys(H+) which likely is helical in the gas phase [3]. The gas phase represents a cleanroom environment to study the intrinsic structural properties of peptides. We employ density-functional theory with the PBE functional corrected for dispersion effects [4] to perform extensive replica-exchange ab initio molecular dynamics simulations. We combine findings from simulations with experimental fingerprints from ion-mobility mass-spectrometry and vibrational spectroscopy. As expected, the natural α-peptide Ac-Ala6-Lys(H+) is found to be mostly α-helical at room temperature. For Ac-β2hAla6-Lys(H+) we find both helical and non-helical conformers in the low-energy regime. However, the helical conformations seem to be favored by vibrational entropy. The comparison with experiment points clearly to a helical structure with a hydrogen bond pattern i←i+4 analogous to the α-helix in natural α-peptides. [1] C. Baldauf, H.-J Hofmann, Helv. Chim. Acta, 2012, 95, 2348. [2] J. M. Fernández-Santín et al., Macromolecules 1987, 20, 62; F. López-Carrasquero et al., Macromol. Chem. Phys. 1995, 196, 253. [3] M. F. Jarrold, PCCP, 2007, 9, 1659. [4] A. Tkatchenko, M. Scheffler, PRL, 2009, 102, 073005.