Physicochemical properties of the plasma membrane play an important role in determining the uptake pathways of peptides. Peptides are divided into two main groups based on their structural characteristics. These groups are primary amphipathic peptides and arginine-rich peptides.
Primary amphipathic peptides have hydrophilic and hydrophobic domains. The hydrophilic parts of the peptide orient towards the hydrophilic region of the membrane. The hydrophobic domain of the peptide is positioned parallel to the membrane surface. The positive side chains of the peptide bind to acidic phospholipid headgroups.
Arginine-rich peptides can be taken up directly or indirectly through endocytosis or direct translocation. The presence of a guanidine group on the arginine is important for both of these methods. These groups form electrostatic interactions with the cell surface components. These interactions lead to the formation of a pore. The peptide pore facilitates translocation of the peptide and cargo.
Peptide-phosphate interactions have also been proposed as a mechanism for pore formation. These interactions occur during membrane thinning. This process partitions the membrane into regions rich in phosphate groups. The formation of a peptide-phosphate pore facilitates the penetration of the peptide and cargo.
A number of studies have characterized the physicochemical properties of anionic membranes, as well as the effects of different membrane fluidities. These studies have shown that the uptake of arginine-rich peptides can vary depending on the membrane properties. In addition, different CPPs may have different uptake pathways.
The peptides R9 and TAT have been investigated for their concentration-dependent uptake. These peptides have been shown to have a specific uptake pathway. Depending on the membrane properties and the concentration of the peptide, a peptide may be taken up through an energy-independent or an endocytosis-dependent pathway.