To be folded or to be unfolded?

Abstract

The lack of ordered structure in "natively unfolded" proteins raises a general question: Are there intrinsic properties of amino acid residues that are responsible for the absence of fixed structure at physiological conditions? In this article, we demonstrate that the competence of a protein to be folded or to be unfolded may be determined by the property of amino acid residues to form a sufficient number of contacts in a globular state. The expected average number of contacts per residue calculated from the amino acid sequence alone (using the average number of contacts for 20 amino acid residues in globular proteins) can be used as one of the simple indicators of natively unfolded proteins. The prediction accuracy for the sets of 80 folded and 90 natively unfolded proteins reaches 89% if the expected average number of contacts is used as a parameter and 83% in the case of hydrophobicity. An optimal set of artificial parameters for 20 amino acid residues obtained by Monte Carlo algorithm to maximally separate the sets of 90 natively unfolded and 80 folded proteins demonstrates the upper limit for prediction accuracy, which is 95%.

Figure 1.

Comparison of the mean values of different parameters computed from sequence alone for the set of 90 “natively unfolded” proteins (black circles) and for the set of 80 “ideally” folded proteins (gray circles). All parameters presented here are averaged per residue; one circle corresponds to one protein. Dependence of (A) expected number of contacts, (B) hydrophobicity in the Kyte and Doolittle (1982) scale, and (C) absolute magnitude of net charge on the number of residues in protein. (D) Dependence of net charge on hydrophobicity. (E) Dependence of the optimal set of artificial parameters on the number of residues in protein. (F) Dependence of expected number of contacts on hydrophobicity. Inset demonstrates the standard deviations for considered parameters.

Figure 2.

Histograms representing the distribution of 90 “natively unfolded” proteins (black bars) and 80 “ideally” folded proteins (gray bars) as a function of (A) expected number of contacts, (B) hydrophobicity on the Kyte and Doolittle (1982) scale, (C) absolute magnitude of net charge, and (D) optimal set of artificial parameters. The dashed line representing the optimal border between two groups of proteins is placed in the intersection of their distributions. The dependence of the fraction of proteins predicted incorrectly (i.e., native proteins predicted as natively unfolded and vice versa) on the border position of considered parameters between two sets of proteins: (E) for expected number of contacts, (F) for hydrophobicity, (G) for absolute magnitude of net charge, and (H) for optimal set of artificial parameters.