Microscopic Characterization of GRP1 PH Domain Interaction with Anionic Membranes

Area of Science:

• Biochemistry
• Molecular Biology
• Computational Biophysics

Background:

• The pleckstrin homology (PH) domain of general receptor for phosphoionositides 1 (GRP1-PHD) specifically binds phosphatidylinositol (3,4,5)-triphosphate (PIP3), a key second messenger.
• Understanding GRP1-PHD's membrane interactions is crucial for elucidating its role in cellular signaling.

Purpose of the Study:

• To investigate the binding mechanisms and dynamics of GRP1-PHD on membranes with varying lipid compositions.
• To identify distinct binding modes and quantify the contribution of anionic lipids to GRP1-PHD's membrane affinity.

Main Methods:

• Extensive molecular dynamics (MD) simulations using the highly mobile membrane mimetic (HMMM) model.
• Complementary full membrane simulations, steered membrane unbinding simulations, and metadynamics simulations.

Main Results:

• GRP1-PHD exhibits stable membrane-bound configurations only in the presence of anionic lipids (PIP3 and PS).
• Two distinct PIP3 binding modes (canonical and alternate) were observed, suggesting potential for simultaneous binding of multiple anionic lipids.
• Anionic lipids, particularly PS, increase the binding affinity of GRP1-PHD, slowing its dissociation from the canonical binding site.

Conclusions:

• Concurrent binding of multiple anionic lipids significantly enhances GRP1-PHD's membrane affinity.
• The observed binding modes and lipid interactions directly influence GRP1-PHD's membrane association and subsequent signaling activity.