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A molecular-dynamics (MD) simulation study of two heptapeptides containing α- and β-amino acid residues is presented. According to NMR experiments, the two peptides differ in dominant fold when solvated in MeOH: peptide 3 adopts predominantly β-hairpin-like conformations, while peptide 8 adopts a 14/15-helical fold. The MD simulations largely reproduce the experimental data. Application of NOE atomatom distance restraining improves the agreement with experimental data, but reduces the conformational sampling. Peptide 3 shows a variety of conformations, while still agreeing with the NOE and 3J-coupling data, whereas the conformational ensemble of peptide 8 is dominated by one helical conformation. The results confirm the suitability of the GROMOS 54A7 force field for simulation or structure refinement of mixed α/β-peptides in MeOH.

The importance of β-peptides lies in their ability to mimic the conformational behavior of α-peptides, even with a much shorter chain length, and in their resistance to proteases. To investigate the effect of substitution of β-peptides on their dominant fold, we have carried out a molecular-dynamics (MD) simulation study of two tetrapeptides, Ac-(2R,3S)-β2,3hVal(αMe)-(2S)-β2hPhe-(R)-β3hLys-(2R,3S)-β2,3-Ala(αMe)-NH2, differing in the substitution at the Cα of Phe2 (pepF with F, and pepH with H). Three simulations, unrestrained (UNRES), using 3J-coupling biasing with local elevation in combination with either instantaneous (INS) or time-averaging (AVE) NOE distance restraining, were carried out for each peptide. In the unrestrained simulations, we find three (pepF) and two (pepH) NOE distance bound violations of maximally 0.22 nm that involve the terminal residues. The restrained simulations match both the NOE distance bounds and 3J-values derived from experiment. The fluorinated peptide shows a slightly larger conformational variability than the non-fluorinated one.

We present a molecular-dynamics simulation study of an α-heptapeptide containing an α-aminoisobutyric acid (=2-methylalanine; Aib) residue, Val1-Ala2-Leu3-Aib4-Ile5-Met6-Phe7, and a quantum-mechanical (QM) study of simplified models to investigate the propensity of the Aib residue to induce 310/α-helical conformation. For comparison, we have also performed simulations of three analogues of the peptide with the Aib residue being replaced by L-Ala, D-Ala, and Gly, respectively, which provide information on the subtitution effect at C(α) (two Me groups for Aib, one for L-Ala and D-Ala, and zero for Gly). Our simulations suggest that, in MeOH, the heptapeptide hardly folds into canonical helical conformations, but appears to populate multiple conformations, i.e., C7 and 310-helical ones, which is in agreement with results from the QM calculations and NMR experiments. The populations of these conformations depend on the polarity of the solvent. Our study confirms that a short peptide, though with the presence of an Aib residue in the middle of the chain, does not have to fold to an α-helical secondary structure. To generate a helical conformation for a linear peptide, several Aib residues should be present in the peptide, either sequentially or alternatively, to enhance the propensity of Aib-containing peptides towards the helical conformation. A correction of a few of the published NMR data is reported.