Capturing spontaneous partitioning of peripheral proteins using a biphasic membrane-mimetic model

Area of Science:

• Biophysics
• Computational Biology
• Protein Science

Background:

• Peripheral protein membrane binding is vital for biological function.
• Computational membrane insertion studies are hindered by long timescales and unknown protein anchors.
• Slow lipid diffusion complicates simulations of protein-membrane interactions.

Purpose of the Study:

• To develop and validate a simplified biphasic solvent model for efficient all-atom molecular dynamics simulations of protein membrane insertion.
• To investigate the hydrophobic insertion of membrane anchoring domains, specifically the GLA domain of human protein C.
• To reduce computational cost while accurately capturing protein-membrane binding events.

Main Methods:

• Development of a biphasic solvent model representing the membrane.
• All-atom molecular dynamics simulations of protein insertion using the simplified model.
• Analysis of protein configurations, including orientation and insertion depth, from multiple starting points.

Main Results:

• The biphasic solvent model efficiently captures hydrophobic insertion of membrane anchoring domains.
• The 'keel' region was consistently identified as the hydrophobic anchor for the GLA domain.
• Simulations yielded convergent results for protein height (2.20 ± 1.04 Å) and angle (23.37 ± 12.48°).
• The model achieved results comparable to full membrane models with an order of magnitude decrease in computational time.

Conclusions:

• The simplified biphasic solvent model offers a computationally efficient alternative for studying protein-membrane interactions.
• This approach enables more exhaustive searches for correct membrane-bound configurations.
• The model accurately predicts protein anchor regions and binding orientations.