Galvani Offset Potential and Constant-pH Simulations of Membrane Proteins

Area of Science:

• Computational Biophysics
• Molecular Dynamics Simulations
• Biomolecular Systems

Background:

• Accurate treatment of titratable residues is crucial for molecular dynamics simulations of large biological systems.
• Conventional methods fix ionization states, limiting realistic modeling.
• Constant-pH simulation methods offer a more dynamic and accurate approach.

Purpose of the Study:

• To address challenges in constant-pH simulations related to the Galvani potential in long-range Coulomb interactions.
• To clarify the effect of the Galvani potential on charging free-energy calculations.
• To introduce a practical solution for constant-pH simulations, specifically for acid-sensing ion channels (ASICs).

Main Methods:

• Utilizing constant-pH simulation methods that allow statistical variation of residue ionization states.
• Extending molecular mechanics (MM) potential energy functions to include different ionization states.
• Analyzing the impact of the Galvani potential on free-energy calculations within periodic boundary conditions.

Main Results:

• Protonation/deprotonation events alter total charge, complicating long-range Coulomb interactions in simulations.
• Charging free-energy calculations in aqueous solution are influenced by the bulk water Galvani potential.
• A practical solution for mitigating Galvani potential effects in constant-pH simulations was developed and applied to ASICs.

Conclusions:

• Constant-pH simulations provide a more realistic treatment of titratable residues compared to fixed-state methods.
• Understanding and correcting for the Galvani potential is essential for accurate free-energy calculations in constant-pH simulations.
• The proposed solution enhances the reliability of constant-pH simulations for systems like ASICs.