Constant-pH MD Simulations of DMPA/DMPC Lipid Bilayers

Area of Science:

• Biophysics
• Computational Chemistry
• Membrane Biology

Background:

• Constant-pH molecular dynamics (CpHMD) accurately models pH effects on soluble biomolecules.
• Simulating pH effects on lipid membranes has been challenging due to environmental complexities.
• Lipid ionization is crucial for biological processes at physiological pH.

Purpose of the Study:

• To develop and apply a constant-pH molecular dynamics (CpHMD-L) method for lipid membrane simulations.
• To investigate the impact of pH on the ionization, phase behavior, and mechanical properties of phospholipid bilayers.
• To provide a more realistic simulation of lipid bilayers by including phospholipid titration.

Main Methods:

• Application of the recent CpHMD-L method.
• Simulation of a 25% DMPA/DMPC bilayer membrane model at different pH values (pH 4 and pH 7).
• Analysis of lipid phases, ionization, and mechanical properties.

Main Results:

• The CpHMD-L method successfully reproduced gel-fluid coexistence at pH 4 and a fluid phase at pH 7.
• Significant transitions in membrane ionization and mechanical properties were observed at physiological pH.
• pH-induced phosphatidic acid (PA)-PA lipid aggregation was observed at acidic pH, consistent with experimental findings.
• This study represents the first simulation of a continuous phospholipid bilayer with titration of all constituent lipids.

Conclusions:

• The CpHMD-L method enables realistic simulations of pH effects on lipid bilayers.
• Phospholipid ionization significantly influences membrane properties and behavior.
• This methodology provides molecular insights into the role of phosphatidic acid in cellular regulation.