Trimethylamine N-oxide influence on the backbone of proteins: an oligoglycine model

Abstract

The study of organic osmolytes has been pivotal in demonstrating the role of solvent effects on the protein backbone in the folding process. Although a thermodynamic description of the interactions between the protein backbone and osmolyte has been well defined, the structural analysis of the effect of osmolyte on the protein backbone has been incomplete. Therefore, we have performed simulations of a peptide backbone model, glycine(15), in protecting osmolyte trimethylamine N-oxide (TMAO) solution, in order to determine the effect of the solution structure on the conformation of the peptide backbone. We show that the models chosen show that the ensemble of backbone structures shifts toward a more collapsed state in TMAO solution as compared with pure water solution. The collapse is consistent with preferential exclusion of the osmolyte caused by unfavorable interactions between osmolyte and peptide backbone. The exclusion is caused by strong triplet correlations of osmolyte, water, and peptide backbone. This provides a clear mechanism showing that even a modest concentration of TMAO forces the protein backbone to adopt a more collapsed structure in the absence of side chain effects.

Figure 1

Radius of gyration probability profile. Black is for the peptide backbone in water solution and red is for the peptide backbone in TMAO solution.

Figure 2

Distance between Cα pairs (a) Numbering of Cα atoms. (b–e) Probability profile for distance between Cα pairs. Black is the peptide backbone in pure water solution and red is for the peptide backbone in TMAO solution. (b) Cα1–Cα15 (c) Cα2–Cα14 (d) Cα3–Cα13 (e) Cα4–Cα11

Figure 3

Representative structures from the two highest populated clusters from Table 1. (a) most populated cluster in water solution (b) second most populated cluster in water solution (c) most populated cluster in TMAO solution (d) second most populated cluster in TMAO solution

Figure 4

Preferential interaction parameter, Γ_{os, bb} as a function of cutoff distance between local and bulk domains.

Figure 5

Representative snapshot from the aqueous TMAO simulation demonstrating solvation of TMAO, water and peptide backbone. Peptide backbone in center with first hydration shell (within 4.0Å from the peptide surface) waters (black) and TMAO (yellow). Orange TMAO molecules that are excluded from the first hydration shell of the peptide, yet still influence the hydration shell of the peptide. Purple waters represent second hydration waters of the peptide (8Å from the peptide).