The Lifson-Roig Model (LRM) and all its variants describe the α-helix to coil transition in terms of additive component free energies within a free energy decomposition scheme, and these contributions are interpreted through sequence-context dependent nucleation and propagation parameters. Although this phenomenological approach is able to adequately fit experimental data on helix content and heat capacity, the number of required parameters increases dramatically with additional sequence variation. Moreover, due to nonadditive competing microscopic effects that are difficult to disentangle within a LRM, large uncertainties within the parameters emerge. We offer an alternative view that removes the need for sequence-context parameterization by focusing on individual microsopic interactions within a free energy decomposition and explicitly account for nonadditivity in conformational entropy through network rigidity using a Distance Constraint Model (DCM). We apply a LRM and a DCM to previously published experimental heat capacity and helix content data for a series of heterogeneous polypeptides. Both models describe the experimental data well, and the parameters from both models are consistent with prior work. However, the number of DCM parameters is independent of sequence-variability, the parameter values exhibit better transferability, and the helix nucleation is predicted by the DCM explicitly through the nonadditive nature of conformational entropy. The importance of these results is that the DCM offers a system-independent approach for modeling stability within polypeptides and proteins, where the demonstrated accuracy for the α-helix to coil transition over a series of heterogeneous polypeptides described here is one case in point.

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