Predicting unfolding thermodynamics and stable intermediates for alanine-rich helical peptides with the aid of coarse-grained molecular simulation

•A 4bAA-CG model predicted helical polypeptide unfolding thermodynamics.•Unfolding intermediates were mediated by hydrophobic contacts between peptides.•Inter-peptide interactions modify the unfolding of individual peptides.

This report focuses on the molecular-level processes and thermodynamics of unfolding of a series of helical peptides using a coarse-grained (CG) molecular model. The CG model was refined to capture thermodynamics and structural changes as a function of temperature for a set of published peptide sequences. Circular dichroism spectroscopy (CD) was used to experimentally monitor the temperature-dependent conformational changes and stability of published peptides and new sequences introduced here. The model predictions were quantitatively or semi-quantitatively accurate in all cases. The simulations and CD results showed that, as expected, in most cases the unfolding of helical peptides is well described by a simply 2-state model, and conformational stability increased with increased length of the helices. A notable exception in a 19-residue helix was when two Ala residues were each replaced with Phe. This stabilized a partly unfolded intermediate state via hydrophobic contacts, and also promoted aggregates at higher peptide concentrations.

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