Abstract
Solvation is critical for protein structural dynamics. Spectroscopic studies have indicated relationships between protein and solvent dynamics, and rates of gas binding to heme proteins in aqueous solution were previously observed to depend inversely on solution viscosity. In this work, the solvent-compatible enzyme Candida antarctica lipase B, which functions in aqueous and organic solvents, was modeled using molecular dynamics simulations. Data was obtained for the enzyme in acetonitrile, cyclohexane, n-butanol, and tert-butanol, in addition to water. Protein dynamics and solvation shell dynamics are characterized regionally: for each α-helix, β-sheet, and loop or connector region. Correlations are seen between solvent mobility and protein flexibility. So, does local viscosity explain the relationship between protein structural dynamics and solvation layer dynamics? Halle and Davidovic presented a cogent analysis of data describing the global hydrodynamics of a protein (tumbling in solution) that fits a model in which the protein's interfacial viscosity is higher than that of bulk water's, due to retarded water dynamics in the hydration layer (measured in NMR τ2 reorientation times). Numerous experiments have shown coupling between protein and solvation layer dynamics in site-specific measurements. Our data provides spatially-resolved characterization of solvent shell dynamics, showing correlations between regional solvation layer dynamics and protein dynamics in both aqueous and organic solvents. Correlations between protein flexibility and inverse solvent viscosity (1/η) are considered across several protein regions and for a rather disparate collection of solvents. It is seen that the correlation is consistently higher when local solvent shell dynamics are considered, rather than bulk viscosity. Protein flexibility is seen to correlate best with either the local interfacial viscosity or the ratio of the mobility of an organic solvent in a regional solvation layer relative to hydration dynamics around the same region. Results provide insight into the function of aqueous proteins, while also suggesting a framework for interpreting and predicting enzyme structural dynamics in non-aqueous solvents, based on the mobility of solvents within the solvation layer. We suggest that Kramers' theory may be used in future work to model protein conformational transitions in different solvents by incorporating local viscosity effects.
Highlights
When it comes to protein structure-dynamics, it is clear that solvent matters
The root mean square fluctuation (RMSF) values for simulations run in Amber force field are in Figure S6 of Supporting Information, and it can be seen that the protein dynamics are virtually identical in every solvent, regardless of force field
What if enzyme structures leverage a similar strategy, by maintaining high mobility in solvation shell waters around regions where more flexibility is required? The hydration dynamics around the Candida antarctica lipase B (CALB) surface were shown in our simulations to be heterogeneous
Summary
When it comes to protein structure-dynamics, it is clear that solvent matters. decades of experiments have shown that solvent dynamics and protein dynamics are intimately related. Protein-solvent dynamics connections were observed in solvent-dependent gas-binding rates to heme, myoglobin, and hemoglobin. Beece et al used flash photolysis to measure gas binding rates to heme proteins in aqueous solutions of different viscosities (Beece et al, 1980). Their data showed that transition rates between different protein conformations are a function of solvent viscosity. Since ligand diffusion and protein dynamics are examples of thermal, or Brownian, motion, the dependence of protein dynamics on solvent dynamics can be understood to arise from the friction of the local solvation environment, represented as solvent viscosity (albeit a local or interfacial measure of viscosity)
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