Protein collapse driven against solvation free energy without H-bonds

Abstract

Proteins collapse and fold because intramolecular interactions and solvent entropy, which favor collapse, outweigh solute-solvent interactions that favor expansion. Since the protein backbone actively participates in protein folding and some intrinsically disordered proteins are glycine rich, oligoglycines are good models to study the protein backbone as it collapses, both during conformational changes in disordered proteins and during folding. The solvation free energies of short glycine oligomers become increasingly favorable as chain length increases. In contrast, the solubility limits of glycine oligomers decrease with increasing chain length, indicating that peptide-peptide, and potentially solvent-solvent interactions, overcome peptide-solvent interactions to favor aggregation at finite concentrations of glycine oligomers. We have recently shown that hydrogen- (H-) bonds do not contribute significantly to the concentration-based aggregation of pentaglycines but that dipole-dipole (CO) interactions between the amide groups on the backbone do. Here we demonstrate for the collapse of oligoglycines ranging in length from 15 to 25 residues similarly that H-bonds do not contribute significantly to collapse but that CO dipole interactions do. These results illustrate that some intrapeptide interactions that determine the solubility limit of short glycine oligomers are similar to those that drive the collapse of longer glycine peptides.

Keywords: intrinsically disordered proteins; molecular dynamics; oligoglycine; simulation.

Figure 1

Probability distributions of the radius of gyration (R _g) for oligoglycines with 5 (Gly₅), 15 (Gly₁₅), and 25 (Gly₂₅) monomers and N‐methylated decaglycine (NMe‐Gly₁₀). Representative snapshots of Gly₁₅ (R _g of 7 Å) and NMe‐Gly₁₀ (R _g of 8 Å) are shown as a green model figure and cyan model figure respectively.

Figure 2

Normalized dipole–dipole correlations ( $〈{\mu }_i·{\mu }_j\left(r\right)〉$) as functions of distance in single oligoglycines of varying lengths at infinite dilution and in phase‐separated clusters containing 625 pentaglycines. Note that the curve for the clustered pentaglycine system includes both intrapeptide and interpeptide correlations. Correlations in NMe‐Gly₁₀ are shown in cyan.

Figure 3

Representative snapshot of Gly₁₅ with examples of peptide dipoles (shown as sticks) in conformations that lead to correlations observed in Figure 2. A pair of sequential residues with their dipole moments oriented parallel to each other are shown with C atoms colored magenta, a pair of sequential residues with their dipole moments oriented antiparallel to each other are shown with C atoms colored green, and two nonsequential residues that come together in a parallel orientation (separated by a distance of 4.4 Å) are shown with C atoms colored yellow.

Figure 4

The numbers of hydrogen (H) bonds in oligoglycines (black filled circles) and in clusters of comparable sizes (cyan filled squares) and the numbers of dipole–dipole (CO) interactions between the amide groups in oligoglycine (red, open, inverted triangles) and in clusters of comparable sizes (blue asterisks). CO interactions in NMe‐Gly₁₀ are shown as a green cross.

Figure 5

Average intrapeptide (A) and peptide–water (B) electrostatic energy components of Gly₂₅; and intramolecular (C) and solute–water (D) electrostatic energy components of NMe‐Gly₁₀ versus area respectively.