Ions Modulate Key Interactions between pHLIP and Lipid Membranes.

Area of Science:

• Biophysics
• Computational Biology
• Membrane Biophysics

Background:

• pH-low insertion peptide (pHLIP) facilitates targeted drug delivery to acidic tumor tissues.
• Tumor-specific extracellular acidosis triggers pHLIP's conformational change for membrane insertion.
• Molecular interactions governing pHLIP adsorption to lipid bilayers remain incompletely understood.

Purpose of the Study:

• To elucidate the role of electrostatics in pHLIP-lipid bilayer interactions.
• To investigate how solution ionic strength impacts pHLIP's membrane adsorption and insertion.
• To understand the influence of lipid headgroup composition on pHLIP behavior.

Main Methods:

• Combined biophysical experiments with all-atom molecular dynamics simulations.
• Studied pHLIP interaction with a 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) bilayer.
• Analyzed the effects of varying solution ionic strength on peptide and membrane structure.

Main Results:

• Solution ionic strength modulates pHLIP structure at the membrane surface and insertion pH.
• Increased ionic strength led to sodium ion coordination with pHLIP's C-terminus, altering helicity.
• Sodium ion coordination with POPC headgroups induced a condensing effect on the lipid bilayer.

Conclusions:

• Electrostatic interactions, particularly influenced by ionic strength, are critical for pHLIP membrane adsorption.
• Findings provide fundamental insights into environmental factors affecting pH-responsive and cell-penetrating peptides.
• Understanding these interactions is key for optimizing pHLIP-based drug delivery systems.