Molecular dynamics at constant pH and reduction potential: application to cytochrome c(3)

Area of Science:

• Biophysical Chemistry
• Computational Biology
• Molecular Dynamics

Background:

• Accurate simulation of redox-active proteins is crucial for understanding biological electron transfer.
• Previous molecular dynamics (MD) simulations at constant pH have limitations in accurately capturing redox behavior.
• Cytochrome c(3) from Desulfovibrio vulgaris Hildenborough serves as a model system for studying complex redox processes.

Purpose of the Study:

• To introduce a novel implementation of the stochastic titration method for MD simulations.
• To enable simulations at both constant pH and constant reduction potential.
• To investigate the redox titration of cytochrome c(3) and the influence of simulation parameters.

Main Methods:

• Extended the stochastic titration method for combined constant pH and reduction potential simulations.
• Performed MD simulations on cytochrome c(3) from Desulfovibrio vulgaris Hildenborough.
• Systematically varied the dielectric constant assigned to the protein environment.

Main Results:

• The enhanced stochastic titration method demonstrated improved performance with a high dielectric constant for the protein.
• Observed strong heme-heme interactions, particularly at lower dielectric constants, impacting simulation accuracy.
• Quantified the coupling between hemes and their sensitivity to pH changes.

Conclusions:

• The choice of protein dielectric constant significantly affects the accuracy of constant pH/redox potential MD simulations.
• The new method provides insights into heme-heme interactions and their influence on redox properties.
• This work advances the simulation of metalloproteins and their electrochemical behavior.