PX- and FYVE-mediated interactions with membranes: simulation studies.

Area of Science:

• Biochemistry
• Computational Biology
• Molecular Biophysics

Background:

• Phosphoinositides, particularly phosphatidylinositol 3-phosphate (PI(3)P), are crucial signaling molecules.
• Specific protein domains, such as FYVE and PX, are known to bind PI(3)P and mediate cellular processes.
• Understanding the precise interactions of these domains with lipid bilayers is essential for elucidating their function.

Purpose of the Study:

• To investigate the interactions of the EEA1-FYVE and p40(phox)-PX domains with PI(3)P and phospholipid bilayers.
• To determine the effect of ligand and membrane binding on the dynamic flexibility and location of these domains.
• To characterize specific and nonspecific lipid-protein interactions at the molecular level.

Main Methods:

• Molecular dynamics (MD) simulations were employed to model protein-lipid interactions.
• Simulations were performed for both apo-state proteins and proteins bound to Ins(1,3)P(2) or PI(3)P.
• Analysis focused on domain location relative to the bilayer and interactions with membrane phospholipids.

Main Results:

• Both FYVE and PX domains exhibited decreased dynamic flexibility upon binding to PI(3)P and the lipid bilayer.
• Domains showed increased penetration into the lipid bilayer compared to initial docked positions.
• FYVE domain's N-terminal region and PX domain's alpha1-alpha2 and beta1-beta2 regions were involved in nonspecific lipid interactions.
• Stable hydrogen bonds were observed between basic side chains and PI(3)P for both domains, though with more fluctuations for FYVE.

Conclusions:

• Protein-ligand and protein-membrane binding significantly alters the dynamics and membrane association of FYVE and PX domains.
• MD simulations provide valuable insights into protein-bilayer interactions, complementing experimental data.
• This computational approach can be extended to predict interactions for other PI-binding proteins.