The project team conducted all-atom molecular dynamics simulations to study the effects of peptide concentration and arrangement on the functionalised nanoparticle efficacy for membrane permeation.
Functional nanomaterials are attracting strong interest as potential target-specific drug delivery vehicles or nanocarriers. A biologically-inspired set of peptides collectively known as cell-penetrating peptides (CPPs) has become an increasingly popular tool for transfection and other types of cellular delivery. This popularity is due to the relative simplicity of synthesizing and attaching these peptides and to the fact that they are able to allow the delivery of a range of molecules including proteins and DNA. Despite such extensive application, the mechanism of action of CPPs is still a subject of debate. One of the most thoroughly studied CPPs is the HIV-derived trans-activator of transcription peptide, TAT. Contrary to initial beliefs, TAT-mediated cell entry is not a purely passive process.
Recent studies have conclusively demonstrated that at least some of the uptake is governed by a type of endocytosis. What remains unknown is whether there is a simultaneous energy-independent mode of transport, i.e. direct diffusion through the cell membrane. Some studies show that TAT can cross artificial bilayers while others show that it cannot. The situation becomes even more complicated when studying the interaction of TAT-functionalised nanomaterials with cell membranes. In vitro experiments have demonstrated that CPPs can allow cellular uptake of nanoparticles and vesicles, but detailed examinations of how the nanomaterial surface affects peptide efficacy have been limited.
The work of Professor Stevens on TAT functionalised nanoparticles highlighted that the physicochemical properties, presentation and local environment of functionalised nanoparticles affect cellular uptake.
- N. Todorova, C. Chiappini, M. Mager, B. Simona, I. I. Patel, M. M. Stevens, I. Yarovsky “Surface presentation of functional peptides in solution determines cell internalization efficiency of TAT conjugated nanoparticles“ Nano Lett, Vol. 14, pp. 5229−5237 (2014)
- N. Todorova, M. Mager, M. Stevens, I. Yarovsky “Structure and dynamics of Tat peptide functionalised gold nanoparticles: Impact on membrane permeability“ RICT2012, Poitiers, France, 2012
- N. Todorova “Proteins under stress need more understanding“ Health Innovations Research Institute Research Day, Melbourne, 2012
- N. Todorova, M. Mager, M. Stevens, I. Yarovsky “HIV1-TAT Peptide modified nanoparticles: when less is more!“ 3rd COMBINE Symposium, Melbourne, Australia, 2012
- N. Todorova, M. Mager, M. Stevens, I. Yarovsky “HIV-TAT Peptide modified nanoparticles: when less is more!“ The 37th Lorne Conference on Protein Structure and Function, Australia, 2012
- I. Yarovsky, N. Todorova, A. Hung, A. Makarucha “Nanoparticles in biological environment: insights from simulations“ International Congress on Theoretical Biophysics, TheoBio 2011, Madeira, Portugal, 2011
- N. Todorova, M. Mager, M. Stevens, I. Yarovsky “HIV1-TAT Peptide modified nanoparticles: insights from molecular dynamics simulations.“ BioPhysChem2011, Wollongong, Australia, 2011
- N. Todorova, I. Yarovsky “ TAT-CALNN peptide modified nanoparticles in aqueous solution: structural insight from molecular dynamics simulations“ The 36th Lorne Conference on Protein Structure and Function, Lorne, Australia, 2011
- N. Todorova, P. Kirk, I. Yarovsky “TAT Peptide modified nanoparticles in aqueous solution: structure and dynamics from molecular simulations“ The 13th Australian Molecular Modelling Conference, Melbourne, 2010