Effect of peptide conformation on membrane permeability

Area of Science:

• Biochemistry
• Membrane Biophysics
• Medicinal Chemistry

Background:

• Peptide conformational constraint influences biological activity and membrane interactions.
• Cyclic peptides, such as c[d-Pen2, d-Pen5] enkephalin (DPDPE), offer potential therapeutic advantages but their membrane permeability is often limited.
• Understanding the factors governing peptide permeation is crucial for drug design.

Purpose of the Study:

• To investigate the impact of conformational constraint on peptide permeation across model membranes.
• To compare the permeability of cyclic and acyclic peptides related to DPDPE.
• To elucidate the thermodynamic basis for differences in membrane interaction between cyclic and acyclic peptides.

Main Methods:

• Determining the permeability of paired cyclic and acyclic peptides across model membranes.
• Synthesizing cyclic peptides via disulfide bridge formation (d-penicillamine or cysteine).
• Utilizing isothermal titration calorimetry to study peptide-membrane interactions.

Main Results:

• Acyclic peptides were 3-7 times more permeable than their cyclic analogs.
• Membrane binding of acyclic Trp6-DPDPE was more exothermic than its cyclic counterpart.
• Acyclic peptide transfer to membrane is enthalpy-driven; cyclic peptide transfer is entropy-driven.

Conclusions:

• Conformational constraint significantly reduces peptide permeability across model membranes.
• Differences in permeability are linked to greater conformational freedom and distinct thermodynamic driving forces for acyclic peptides.
• These findings have implications for designing peptides with improved membrane transport properties.