On the Influence of Charged Side Chains on the Folding-Unfolding Equilibrium of β-Peptides: A Molecular Dynamics Simulation Study

The influence of charged side chains on the folding–unfolding equilibrium of β‐peptides was investigated by means of molecular dynamics simulations. Four different peptides containing only negatively charged side chains, positively charged side chains, both types of charged side chains (with the ability to form stabilizing salt bridges) or no charged side chains were studied under various conditions (different simulation temperatures, starting structures and solvent environment). The NMR solution structure in methanol of one of the peptides (A) has already been published; the synthesis and NMR analysis of another peptide (B) is described here. The other peptides (C and D) studied herein have hitherto not been synthesized. All four peptides A–D are expected to adopt a left‐handed 314‐helix in solution as well as in the simulations. The resulting ensembles of structures were analyzed in terms of conformational space sampled by the peptides, folding behavior, structural properties such as hydrogen bonding, side chain–side chain and side chain–backbone interactions and in terms of the level of agreement with the NMR data available for two of the peptides. It was found that the presence of charged side chains significantly slows down the folding process in methanol solution due to the stabilization of intermediate conformers with side chain–backbone interactions. In water, where the solvent competes with the solute–solute polar interactions, the folding process to the 314‐helix is faster in the simulations. The folding–unfolding equilibrium influenced by charged side chains has been analyzed by molecular dynamics simulation for four peptides A–D (one example shown), which are expected to adopt a left‐handed 314‐helix in solution as well as in the simulations. The resulting ensembles of structures were analyzed in terms of conformational space sampled by the peptides, folding behavior, structural properties such as hydrogen bonding, side‐chain–side chain and side‐chain–backbone interactions and in terms of the level of agreement with the NMR data available for two of the peptides.