Alpha- and beta-polypeptides show a different stability of helical secondary structure Thereza Soares, Markus Christen, Kaifeng Hu and Wilfred F. van Gunsteren * Laboratory of Physical Chemistry, Swiss Federal Institute of Technology Zurich ETH, Ho ¨nggerberg, CH-8093 Zu ¨rich, Switzerland Received 7 April 2004; revised 28 May 2004; accepted 8 June 2004 Available online 2 July 2004 Abstract—b-Polypeptides are known to adopt helical secondary structure in organic solvents, even for rather short chain lengths. It is investigated whether a short a-polypeptide with amino-acid side chains that enable b-peptides to adopt helical structures, can maintain or adopt stable helical structure in methanol or in water. The molecular dynamics simulations do not predict a particular fold, which indicates an essential role for the additional methylene moiety in the backbone of b-peptides regarding helix stability. q 2004 Elsevier Ltd. All rights reserved. 1. Introduction In aqueous solution proteins, that is, long polypeptide chains of a particular composition of a-amino acid residues, generally adopt a specific tertiary structure or fold. Shorter a-polypeptides in the range of 10–30 residues may adopt secondary structure, such as a-helices or b-sheets, but their fold generally becomes less stable the shorter the polypep- tide chain. In contrast, polypeptides made up of b-amino acids are known to adopt rather stable helical or b-sheet structures even for very short chain lengths of 4 – 7 residues, in particular when solvated in an organic solvent such as methanol. 1,2 Accordingly, short b-polypeptides are suitable molecules to investigate polypeptide stability and folding mechanism. 3–5 Yet, one may ask why short a-polypeptides do not adopt stable secondary structure. Is this due to their different backbone composition compared to b-peptides, or to the solvation effects of water compared to methanol, or to differences in side-chain sequences of the a- and b-polypeptides studied experimentally? Here, we address this question through molecular dynamics (MD) simulation of a 7-residue a-peptide (Val, Ala, Leu, Aib, Ile, Met, Phe) solvated both in methanol and in water. The a-amino acid composition has been proposed by our colleagues Jaun and Seebach in analogy to the b-amino acid sequence (Val, Ala, Leu, di-Ala, Val, Ala, Leu) of a 7 residue b-peptide that exhibits a rather stable 3 14 -helical fold in methanol. 6 In this b-heptapeptide all side chains are at the b-carbon and the central residue is substituted with a methyl group at the a-carbon in addition. In order to facilitate the interpretation of NMR spectra to be measured all residues were chosen to be different. The central Aib residue should promote helix formation. 7 We investigate whether this a-heptapeptide that was designed to adopt a helical fold, will indeed maintain or adopt an a-helical conformation in methanol or in water. The a-heptapeptide has been simulated for 26 ns in methanol and for 7.8 ns in water, both starting from an ideal a-helical initial structure and starting from a wholly extended backbone structure (Fig. 1). Because of the higher density of interacting atoms, the simulation in water is three 0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.tet.2004.06.062 Tetrahedron 60 (2004) 7775–7780 Figure 1. Panel A. Chemical formula of the a-heptapeptide studied. Panel B. a-Helical conformation of the peptide. * Corresponding author. Tel.: þ41-1-632-68-61; fax: þ41-1-632-10-39; e-mail address: wfvgn@igc.phys.chem.ethz.ch Keywords: Alpha-peptide; Beta-peptide; Molecular dynamics simulation; Peptide folding; Conformation analysis.