Principles of carbopeptoid folding: a molecular dynamics simulation study

The conformational spaces of five oligomers of tetrahydrofuran-based carbopeptoids in chloroform and dimethyl sulfoxide were investigated through nine molecular dynamics simulations. Prompted by nuclear magnetic resonance experiments that indicated various stable folds for some but not all of these carbopeptoids, their folding behaviour was investigated as a function of stereochemistry, chain length and solvent. The conformational distributions of these molecules were analysed in terms of occurrence of hydrogen bonds, backbone torsional-angle distributions, conformational clustering and solute configurational entropy. While a cis-linkage across the tetrahydrofuran ring favours right-handed helical structures, a trans-linkage results in a larger conformational variability. Intra-solute hydrogen bonding is reduced with increasing chain length and with increasing solvent polarity. Solute configurational entropies confirm the picture obtained: they are smaller for cis- than for trans-linked peptides, for chloroform than for dimethyl sulfoxide as solvent and for shorter peptide chains. The simulations provide an atomic picture of molecular conformational variability that is consistent with the available experimental data.