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Spatially resolved free-energy contributions of native fold and molten-globule-like Crambin.

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Heinz,  L. P.
Department of Theoretical and Computational Biophysics, MPI for biophysical chemistry, Max Planck Society;

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Grubmüller,  H.
Department of Theoretical and Computational Biophysics, MPI for biophysical chemistry, Max Planck Society;

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Citation

Heinz, L. P., & Grubmüller, H. (2021). Spatially resolved free-energy contributions of native fold and molten-globule-like Crambin. Biophysical Journal, 120, 3470-3482. doi:10.1016/j.bpj.2021.05.019.


Cite as: https://hdl.handle.net/21.11116/0000-000A-CB5E-9
Abstract
The folding stability of a protein is governed by the free-energy difference between its folded
and unfolded states, which results from a delicate balance of much larger but almost compensating
enthalpic and entropic contributions. The balance can therefore easily be shifted by an external
disturbance, such as a mutation of a single amino acid or a change of temperature, in which case the
protein unfolds. Effects like cold denaturation, in which a protein unfolds due to cooling, provide
evidence that proteins are strongly stabilized by the solvent entropy contribution to the free energy
balance. However, the molecular mechanisms behind this solvent-driven stability, their quantitative
contribution in relation to other free-energy contributions, and how the involved solvent thermodynamics
is affected by individual amino acids, is largely unclear. Therefore, we addressed these questions using
atomistic molecular dynamics simulations of the small protein Crambin in its native fold and a molten-
globule-like conformation, which here served as a model for the unfolded state. The free-energy
difference between these conformations was decomposed into enthalpic and entropic contributions from
the protein and spatially resolved solvent contributions using the non-parametric method Per|Mut. From
the spatial resolution, we quantified the local effects on the solvent free-energy difference at each amino
acid and identified dependencies of the local enthalpy and entropy on the protein curvature. We
identified a strong stabilization of the native fold by almost 500 kJ*mol(-1) due to the solvent entropy,
revealing it as an essential contribution to the total free-energy difference of (53 +/- 84) kJ*mol(-1) .
Remarkably, more than half of the solvent entropy contribution arose from induced water correlations.