The mechanism of cold denaturation in proteins is often incompletely understood due to limitations in accessing the denatured states at extremely low temperatures. Using atomistic molecular dynamics simulations, we have compared early (nanosecond timescale) structural and solvation properties of yeast frataxin (Yfh1) at its temperature of maximum stability, 292 K (Ts), and the experimentally observed temperature of complete unfolding, 268 K (Tc). Within the simulated timescales, discernible “global” level structural loss at Tc is correlated with a distinct increase in surface hydration. However, the hydration and the unfolding events do not occur uniformly over the entire protein surface, but are sensitive to local structural propensity and hydrophobicity. Calculated infrared absorption spectra in the amide-I region of the whole protein show a distinct red shift at Tc in comparison to Ts. Domain specific calculations of IR spectra indicate that the red shift primarily arises from the beta strands. This is commensurate with a marked increase in solvent accessible surface area per residue for the beta-sheets at Tc. Detailed analyses of structure and dynamics of hydration water around the hydrophobic residues of the beta-sheets show a more bulk water like behavior at Tc due to preferential disruption of the hydrophobic effects around these domains. Our results indicate that in this protein, the surface exposed beta-sheet domains are more susceptible to cold denaturing conditions, in qualitative agreement with solution NMR experimental results.
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See supplementary material at http://dx.doi.org/10.1063/1.4901897 for IR absorption spectra for H1; distributions of tetrahedral order parameter (Q) for bulk and hydration water of hydrophobic domains; plots of protein-water radial distribution function, g(r) for Ubq, and Δg(r) between Tc and Th for Ubq and Yfh1; plots of g(r) of different domains of Ubq and Yhf1; P(n*) distributions for BetaH and HelixH of Ubq at Tc and Ts; comparative plots of P(n*) distributions around different domains of Yfh1 at Tc and Th; Schlitter's method; comparative cumulative configurational entropy plots of Yfh1 at Tc, Ts, and Th; tabulated values of SASA per residue in Yfh1 and their change in values from Ts to Tc.
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