PENETRATING PEPTIDES · Cell penetrating peptides: Modelling trans-membrane insertion
FP6 — Marie Curie Actions (Human Resources and Mobility)
- Duration
- 2008-05-01 → 2008-11-30
- EU contribution
- €24,500
- Participants
- 1
- Scheme
- IIF
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Results in brief
Final Activity Report Summary - PENETRATING PEPTIDES (Cell penetrating peptides: Modelling transmembrane insertion)
Cell-penetrating peptides (CPPs) have recently attracted much attention because of their apparent ability to penetrate cell membranes in an energy independent manner. In this project, molecular dynamics simulation techniques were used to study the interaction of two CPPs, i.e. penetratin and the Transactivator of transcription (TAT) peptide with Dipalmitoyl phosphatidylcholine (DPPC) and Dioleylphosphatidylcholine (DOPC) phospholipid bilayers, shedding light on the mechanisms via which these peptides might cross biological membranes. The simulations suggested that the peptides might enter the cell through micropinocytosis. Multiple peptides were observed to induce large deformations in the lipid bilayer in the form of deep grooves, which enclosed aggregated peptides. This structure persisted for the time scale of the simulations, equal to hundreds of nanoseconds. No spontaneous pore formation was observed during the simulations. However, pore formation could be induced in simulations where an external potential was used to pull a single penetratin or TAT peptide into the membrane. Using umbrella sampling techniques the free energy of inserting a single peptide into a DPPC bilayer was estimated to be approximately 75 kJ/mol-1 in the case of penetratin and approximately 120 kJ/mol-1 in the case of TAT peptide, suggesting that penetratin was more likely to translocate spontaneously through the membrane than TAT peptide. It was also evident that penetration of single peptides would require a timescale of at least seconds to minutes. In addition, the work illustrated the extent to which the results of such simulations could be dependent on initial conditions, extent of equilibration, size of the system and conditions under which the simulations were performed.
Data: CORDIS, © European Union
Project objective
The lipid bi-layers of biological membranes are not permeable for hydrophilic molecules under physiological conditions. However, numerous biomedical applications, such as drug delivery and gene therapy, rely on reliable way of the transmembrane translocation of proteins, fragments of DNA and other water-soluble compounds. Thus, the search for possible transduction agents continued for several decades. Cell-penetrating peptides (CPPs) are recognized to be amino acid sequences, which make an effective transduction of the hydrophilic molecules through the cell membrane possible. The transduction is claimed to be spontaneous and energy-independent process. This makes CPPs very attractive for numerous applications. Some of the CPPs are structural parts of natural proteins, while others are purely artificial or engineered sequences. Different molecular cargoes can cross the membrane being covalently bound to CPPs, which is already used in biomedical researches.Although the CPPs are widely studied for more then a decade, their transduction mechanism is still not understood. Several possible models are proposed, however, there are no experimental techniques, which can reveal the molecular details of the translocation process and distinguish between these models. The macroscopic transduction rates of particular CPPs are of great interest for practical applications, but cannot be easily determined experimentally. Molecular dynamics simulations provide unique opportunity to study the transduction of CPPs in atomic details and to measure the transduction rates in any desirable conditions.In the present project extensive molecular dynamics simulations of various lipid bi-layers in the presence of the cell penetrating peptides will be conducted in order to observe the event s of transduction and characterize this process in full molecular details. Transduction rates will be calculated combining the results of MD simulations with theoretical approaches.
Original text from CORDIS.
Participants
- INSTITUTE OF PHYSICS OF THE NATIONAL ACADEMY OF SCIENCE OF UKRAINE · KIEVCoordinatorCity levelUkraine
Links
Data: CORDIS, © European Union