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. 2017 Aug 31;121(34):8078-8084.
doi: 10.1021/acs.jpcb.7b05469. Epub 2017 Aug 21.

Intramolecular Interactions Overcome Hydration to Drive the Collapse Transition of Gly15

D Asthagiri  1   2 , Deepti Karandur  3 , Dheeraj S Tomar  4 , B Montgomery Pettitt  2   3
Affiliations

Intramolecular Interactions Overcome Hydration to Drive the Collapse Transition of Gly15

D Asthagiri et al. J Phys Chem B. .

Abstract

Simulations and experiments show oligo-glycines, polypeptides lacking any side chains, can collapse in water. We assess the hydration thermodynamics of this collapse by calculating the hydration free energy at each of the end points of the reaction coordinate, here taken as the end-to-end distance (r) in the chain. To examine the role of the various conformations for a given r, we study the conditional distribution, P(Rg|r), of the radius of gyration for a given value of r. The free energy change versus Rg, -kBT ln P(Rg|r), is found to vary more gently compared to the corresponding variation in the excess hydration free energy. Using this observation within a multistate generalization of the potential distribution theorem, we calculate a tight upper bound for the hydration free energy of the peptide for a given r. On this basis, we find that peptide hydration greatly favors the expanded state of the chain, despite primitive hydrophobic effects favoring chain collapse. The net free energy of collapse is seen to be a delicate balance between opposing intrapeptide and hydration effects, with intrapeptide contributions favoring collapse.

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Conflict of interest statement

Notes

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
Left panel: PMF, ΔW(r), relative to r = 40 Å for Gly15 folding in the domain r ∈ [20, 40] Å. The PMF obtained from ABF is shown as a solid black line; the statistical uncertainty is below 0.1 kcal/mol (1σ) and is not shown. ○, ΔW (KHP), PMF obtained independently by Karandur, Harris, and Pettitt from large-scale unbiased sampling. Right panel: The change in the internal energy ΔE (red line) and its electrostatic (blue) and van der Waals (gray) contributions for the solvated peptide. Peptide conformations from only the L30 and L40 domains were used in calculating the internal energies. The internal energies are sorted and binned according to r. The light red shading indicates the 2σ standard error of the mean. The contributions from dihedral and angle terms of the force field are negligible on the scale of the graph.
Figure 2
Figure 2
Hydration free energy values for several Gly15 conformations for Rg values of interest in the present study. All calculations are based on all-atom simulations and the regularization approach. The linear fit is solely to indicate that on average μex decreases with increasing Rg, i.e., as more of the chain is exposed to the solvent.
Figure 3
Figure 3
Probability distribution of Rg values for the specified end-to-end distances. For r = 20.1 Å, the Rg of the most collapsed conformation is 5.5 Å, and for r = 39.9 Å, the Rg of the most collapsed conformation is 10.8 Å. These Rg values fall slightly to the left of the leftmost point shown in the plot.
Figure 4
Figure 4
Left panel: The hydration free energy and its components based on the quasichemical decomposition.–,, Right panel: Decomposition of the hydration free energy change into enthalpic and entropic contributions. The enthalpy of hydration is further separated into a solvent reorganization and solute–solvent interaction parts.
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