Salt Effects on Protein Folding Thermodynamics

Area of Science:

• Biophysics
• Computational Biology
• Protein Science

Background:

• Salts significantly impact protein folding thermodynamics and kinetics by altering protein conformations.
• Understanding salt-specific effects is crucial for predicting protein behavior in solution.

Purpose of the Study:

• To develop and validate a coarse-grained protein model for predicting salt-induced changes in protein properties.
• To investigate the influence of seven different salts on the folding thermodynamics of two model proteins: lac-DBD and NTL9.

Main Methods:

• Developed a coarse-grained protein model utilizing transfer free-energy data from water to salt solutions.
• Employed molecular dynamics simulations to probe salt effects on protein folding thermodynamics.
• Calculated thermodynamic properties, including m values, and analyzed protein compaction and transition-state ensembles.

Main Results:

• The model accurately predicts salt-induced changes in protein folding thermodynamics, showing quantitative agreement with experimental m values.
• Salt identity significantly influences protein compaction in the denatured state, with variations from ~4% to ~30%.
• Observed distinct transition-state ensembles (TSEs) for lac-DBD (homogeneous) and NTL9 (heterogeneous), with salts inducing subtle, predictable structural changes.

Conclusions:

• A salt's effect on protein stability is sequence and topology-dependent.
• The developed model provides a reliable tool for predicting salt effects on protein folding.
• Strongly stabilizing salts can significantly reduce or eliminate the protein folding energy barrier at moderate concentrations.