Headgroup Structure and Cation Binding in Phosphatidylserine Lipid Bilayers

Area of Science:

• Biophysics
• Computational Chemistry
• Biochemistry

Background:

• Phosphatidylserine (PS) is crucial for eukaryotic membrane function, involved in protein interactions, membrane fusion, and phase separation, particularly with calcium ions.
• Understanding PS behavior at a molecular level is limited by the lack of accurate computational models for interpreting experimental data.

Purpose of the Study:

• To assess the accuracy of commonly used molecular dynamics (MD) force fields in describing phosphatidylserine (PS) headgroup structure and cation binding.
• To augment existing NMR data with new solid-state NMR measurements to provide a more comprehensive dataset for model validation.

Main Methods:

• Collected and augmented experimental NMR data, including C-H bond order parameter magnitudes and signs, for pure PS and mixed PS:PC lipid bilayers.
• Evaluated the accuracy of multiple classical MD force fields (CHARMM36, Lipid17, MacRog, Slipids, GROMOS-CKP, Berger) against the experimental NMR data.
• Utilized S-DROSS solid-state NMR spectroscopy to determine the signs of order parameters in the PS headgroup.

Main Results:

• Significant discrepancies were observed between different MD force fields, with none accurately reproducing the experimental NMR data.
• While the best MD models could distinguish between PC and PS headgroup structures, cation binding affinity was poorly captured across all tested PS force fields.
• Simulated responses of the PS headgroup to bound ions qualitatively differed from experimental observations.

Conclusions:

• Current classical MD force fields exhibit substantial inaccuracies in modeling PS headgroup structure and cation interactions in lipid bilayers.
• The developed comprehensive experimental dataset and simulation results provide a foundation for creating improved lipid force fields for negatively charged membranes.
• Accurate force fields are essential for reliable computational studies of biologically relevant membrane phenomena.