On hydrophobicity and conformational specificity in proteins

Abstract

In this study we examine the distribution of hydrophobic residues in a nonredundant set of monomeric globular single-domain proteins. We find that the total fraction of hydrophobic residues is roughly constant and has no discernible dependence on protein size. This results in a decrease of the hydrophobicity of the core as the size of proteins increases. Using a normalized measure, and by comparing with sets of randomly reshuffled sequences, we show that this change in the composition of the core is statistically significant and robust with respect to which amino acids are considered hydrophobic and to how buried residues are defined. Comparison with model sequences optimized for stability, while still required to retain their native state as a unique minimum energy conformation, suggests that the size-independence of the total fraction of hydrophobic residues could be a result of requiring proteins to be conformationally specific.

FIGURE 1

(a) The fraction of buried residues, f_b, and the fraction of hydrophobic residues, f_h, as a function of chain length, N with Leu, Ile, Val, Phe, Met, and Trp considered hydrophobic, and residues with ASA < 30% considered buried. (b) f_h with Leu, Ile, Val, Phe, Met, Trp, Cys, Pro, and Ala considered hydrophobic. The data for f_b in a is fitted to a function of the form 1 − α × N^−1/3 with α = 2.43.

FIGURE 2

Shown are for the two sets of hydrophobic residues and for two different cutoffs for defining buried residues as indicated at the top of each figure. The ⋄ shows the averages of in bins of size 100.

FIGURE 3

Data for the HP model. (a) The size-dependence of the average of the fraction of hydrophobic residues, 〈f_h〉, for all designing sequences and for optimized designing sequences. Also shown is the average fraction of core residues, 〈f_c〉, and the average fraction of buried residues, 〈f_b〉, for all designable structures. In b we show the size-dependence of the average fraction of core residues that are hydrophobic, 〈f_ch〉, and the average fraction of buried residues that are hydrophobic, 〈f_bh〉. Shown is data for all designing sequences and for optimized designing sequences.