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Biophysical Studies of Cell-Penetrating Peptides 241
complicated and unlikely as a pore model. Whether any of the CPPs are able to
promote a transverse diffusion (flip-flop) of some phospholipids remains to be
studied.
There is today no simple correlation between any degree of secondary structure
induced in various model systems and the permeability efficiency of CPPs in cellular
systems. Translocation of a charged CPP and a cargo across an intact membrane is
energetically very unfavorable, even in the presence of proper transmembrane potential.
The CPP effect will depend on biophysical phenomena, not easily accounted
for by structures, or molecular simulations in a short time window (~nsec). The
function of the CPP tag could perhaps be as a magic agent to destabilize the
membrane locally. Electrostatic perturbations within the membrane, primarily in the
outer leaflet, may cause lateral rearrangement of acidic lipids. Besides membrane
surface potential, interfacial dipole potential could be influenced. A discreteness-ofcharge
phenomenon may also be created, as suggested for studies on hepta-lysine. 28
A thinning of the membrane like the one reported with magainin, 60 combined with
a reduction of local surface tension, may allow CPPs to intercalate the membrane.
An intimate and flexible sealing between peptide side groups and lipid head groups
will reduce leakage until the CPP slips snugly through and pulls the concomitant
cargo inside. After this transient permeation the membrane must rapidly recover and
heal. The detailed structural and thermodynamic description of such a hypothetic
process remains to be worked out. From the biophysical point of view, to elucidate
the mechanisms involved in CPP translocation and transport is still a challenge.
ACKNOWLEDGMENT
Work on this project in the authors’ laboratory is supported by the Swedish Science
Council.
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