Simulation of electron-proton coupling with a Monte Carlo method: application to cytochrome c3 using continuum...

Area of Science:

• Biophysical Chemistry
• Computational Biology
• Protein Thermodynamics

Background:

• Traditional methods often overlook the full binding equilibrium of electrons and protons.
• This oversight leads to neglecting the impact of binding fluctuations on protein energy and entropy.
• Understanding these fluctuations is key to accurately modeling redox proteins.

Purpose of the Study:

• To present a novel simulation method for simultaneous electron and proton binding equilibrium.
• To investigate the full equilibrium thermodynamics of redox and protonation processes, including electron-proton coupling.
• To provide a more realistic connection between simulations and experimental parameters like pH and electrostatic potential.

Main Methods:

• Simulating simultaneous binding equilibrium of electrons and protons on protein molecules.
• Utilizing a continuum electrostatic method based on the linear Poisson-Boltzmann equation.
• Applying the method to cytochrome c3 from Desulfovibrio vulgaris Hildenborough.

Main Results:

• Successfully predicted the full reduction order of the four hemes in cytochrome c3 at physiological pH.
• Identified key sites involved in the redox-Bohr effect, including propionate D of heme I, His67, the N-terminus, and propionate D of heme IV.
• Quantified significant occupational entropy contributions to midpoint redox potentials and pKa values.

Conclusions:

• The new method offers a more realistic approach to studying protein redox and protonation thermodynamics.
• Binding fluctuations and occupational entropy play significant roles in the behavior of redox proteins.
• The findings advance the understanding of electron-proton coupling and the redox-Bohr effect in proteins.