Fluctuation Relations to Calculate Protein Redox Potentials from Molecular Dynamics Simulations

Area of Science:

• Biochemistry and Biophysics
• Computational Chemistry
• Protein Engineering

Background:

• Tunable protein redox potentials are crucial for biotechnology and catalysis.
• Accurate prediction of redox potential shifts is essential for protein design.

Purpose of the Study:

• To introduce and validate a novel computational method (MD + CB) for calculating redox potential changes in proteins.
• To assess the accuracy and applicability of the MD + CB method for designed protein mutants.

Main Methods:

• Combining fluctuation relations with molecular dynamics (MD) simulations.
• Simulating reduced and oxidized protein states and their interconversion.
• Utilizing Kubo-Onsager approach and Bayesian inference for efficient redox potential estimation.

Main Results:

• The MD + CB method demonstrated reliable performance in predicting redox potential shifts.
• A good correlation (0.85) was observed between MD + CB predictions and experimental values for designed mutants.
• MD + CB results compared favorably with continuum electrostatic methods.

Conclusions:

• The MD + CB approach offers an efficient and accurate way to estimate redox potentials in proteins.
• This method is transferable to standard MD simulations, promising advancements in redox protein engineering and design.