Folding–Unfolding Equilibrium of a Methylidene‐Substituted β‐Peptide

Abstract

Abstractβ‐Peptides possess the ability to fold into secondary structure elements, and this property, together with resistance to biodegradation, makes these compounds interesting for pharmaceutical applications. Recently, a novel class of β‐peptides containing methylidene moieties was described. The GROMOS 53A6 force field was used to simulate the folding equilibrium of a β3‐hexapeptide with methylidene (CH2) groups at all six CA‐atoms. Due to the rotational barriers induced by these methylidene groups, the helical secondary‐structure elements, normally found in β3‐peptides, are disfavored in this molecule. Simulations, started from fully extended and 314‐helical conformations, showed that the molecule adopts a complete 28‐helix for ca. 5% of the time and partial 28‐helical conformations for ca. 20% of the time. Yet, as suggested by experiments, the folding equilibrium is dominated by unfolded conformations.