Development of a rotamer library for use in β-peptide foldamer computational design

Foldamers present a particularly difficult challenge for accurate computational design compared to the case for conventional peptide and protein design due to the lack of a large body of structural data to allow parametrization of rotamer libraries and energies. We therefore explored the use of molecular mechanics for constructing rotamer libraries for non-natural foldamer backbones. We first evaluated the accuracy of molecular mechanics (MM) for the prediction of rotamer probability distributions in the crystal structures of proteins is explored. The van der Waals radius, dielectric constant and effective Boltzmann temperature were systematically varied to maximize agreement with experimental data. Boltzmann-weighted probabilities from these molecular mechanics energies compare well with database-derived probabilities for both an idealized α-helix (R = 0.95) as well as β-strand conformations (R = 0.92). Based on these parameters, de novo rotamer probabilities for secondary structures of peptides built from β-amino acids were determined. To limit computational complexity, it is useful to establish a residue-specific criterion for excluding rare, high-energy rotamers from the library. This is accomplished by including only those rotamers with probability greater than a given threshold (e.g., 10%) of the random value, defined as 1/n where n is the number of potential rotamers for each residue type.