Do Valine Side Chains Have an Influence on the Folding Behavior of β-Substituted β-Peptides?

The influence of valine side chains on the folding/unfolding equilibrium and, in particular, on the 314‐helical propensity of β3‐peptides were investigated by means of molecular‐dynamics (MD) simulation. To that end, the valine side chains in two different β3‐peptides were substituted by leucine side chains. The resulting four peptides, of which three have never been synthesized, were simulated for 150 to 200 ns at 298 and 340 K, starting from a fully extended conformation. The simulation trajectories obtained were compared with respect to structural preferences and folding behavior. All four peptides showed a similar folding behavior and were found to predominantly adopt 314‐helical conformations, irrespective of the presence of valine side chains. No other well‐defined conformation was observed at significant population in any of the simulations. Our results imply that β3‐peptides show a structural preference for 314‐helices independent of the branching nature of the side chains, in contrast to what has been previously proposed on the basis of circular‐dichroism (CD) measurements.