Permeation of the three aromatic dipeptides through lipid bilayers: Experimental and computational study

Area of Science:

• Biophysics
• Computational Chemistry
• Membrane Biology

Background:

• Understanding passive peptide permeation across lipid bilayers is crucial for drug delivery and membrane protein function.
• Aromatic dipeptides serve as model systems for studying peptide-membrane interactions.

Purpose of the Study:

• To investigate the passive permeation of N-acetyl-phenylalanineamide (NAFA), N-acetyltyrosineamide (NAYA), and N-acetyl-tryptophanamide (NATA) through a 1,2-dioleoyl-sn-glycero-3-phospocholine (DOPC) lipid bilayer.
• To elucidate the molecular mechanisms governing peptide translocation and conformational changes within the membrane environment.

Main Methods:

• Time-resolved parallel artificial membrane permeability assay with fluorescence detection.
• Comprehensive computer simulations including umbrella sampling and Smoluchowski equation for calculating potential of mean force and diffusion coefficients.

Main Results:

• NAFA exhibited the fastest permeation, while NAYA showed the slowest, with NATA in between.
• Peptides preferentially bind to the lipid interface and face large free energy barriers in the membrane center.
• Translational diffusion coefficients showed minimal change, but rotational diffusion significantly decreased upon membrane insertion, restricting peptide conformational freedom.

Conclusions:

• The study provides a detailed microscopic understanding of passive peptide permeation.
• Rotational diffusion is a key indicator of peptide conformational changes and interactions within lipid bilayers.
• Findings highlight the complex interplay between peptide structure, membrane environment, and translocation dynamics.