Natively unfolded protein stability as a coil-to-globule transition in charge/hydropathy space.

In the absence of experimental assignments, the empirical charge/hydropathy correlation for the prediction of natively unfolded protein sequences (Uversky, V. N.; Gillespie, J. R.; Fink, A. L. Proteins: Struct., Funct., Genet. 2000, 41, 415-427) provides perhaps the most intuitive description of gross polypeptide conformation. The success of this correlation rests on an essential chain length independence of the boundary line between expanded and compact conformations, conversely stabilized by highly charged/weakly hydrophobic residues or weakly charged/highly hydrophobic residues, respectively. We present extensive simulation results for coarse-grained polypeptides over a wide range of sequence hydrophobicities, charges, and lengths. A coil-to-globule transition in sequence composition space analogous to the charge/hydropathy correlation is observed. A near sequence length independent stability boundary is only found when counterions for the charged peptides are explicitly included, as a result of counterion condensation stabilization of repulsive electrostatic interactions on the globule surface. The observed counterion adsorption is shown to be in quantitative agreement with theoretical condensation predictions. We argue that alternate functionalities, beyond charge and hydrophobicity, empirically known to correlate with conformational disorder can be incorporated into our minimalist polypeptide model to study the interplay between independent predictors of unfolded sequences.