In silico folding of hydrophobic peptides that form β-hairpin structures in solution

Peptides designed with residues that have a high propensity to occur in β-turns form β-hairpin structures in apolar as well as in polar organic solvents such as dimethyl sulfoxide (DMSO). Due to limited solubility, their conformations have not been investigated experimentally in water. We have examined the conformations of four of such designed peptides that fold into well-defined β-hairpin structures facilitated by β-turns, in the crystalline state and in solution, by molecular dynamics simulations (MDS). The peptides folded into β-hairpin structures in water, starting from the fully extended conformation. However, in DMSO, neither folding nor unfolding was observed during MDS, when the starting structures were unfolded and folded, respectively. The lack of folding in DMSO was investigated by constructing folding free energy landscapes by umbrella sampling. The folding free energy landscape is smooth in water, whereas in DMSO, folded and unfolded structures are separated by high-energy barriers. The folding free energy is less in DMSO compared with water due to a more stable unfolded structure in DMSO compared with water, which in turn is due to stabilisation of the unfolded state by hydrophobic interactions in DMSO. This finding will be helpful to researchers to accurately model and/or design small peptide structures in water and organic solvents.