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Computational determination of the binding kinetics of the pH‐Low Insertion Peptide
Author(s) -
Freshwater Kasey,
Flint Bethann,
Mertz Blake
Publication year - 2019
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2019.33.1_supplement.655.2
Subject(s) - popc , chemistry , lipid bilayer , biophysics , membrane , peptide , bilayer , cell membrane , biological membrane , biochemistry , biology
Membrane active peptides (MAPs) have the potential to be utilized in a number of biomedical applications due to their ability to alter the membrane through surface interactions. MAPs with pH‐dependent activity can be harnessed for use in medical imaging and targeted drug delivery to cells afflicted with diseases characterized by acidosis, such as cancer, arthritis, and heart disease. An example of this type of MAP is the pH‐Low Insertion Peptide (pHLIP), which interacts with the membrane in three states: in State I, pHLIP is randomly coiled in solution; upon addition of lipid vesicles, pHLIP binds to the membrane surface and gains partial helicity (State II), and upon acidification, pHLIP fully folds, inserting unidirectionally into the membrane (State III). Currently, the peptide‐membrane interactions leading to formation of stable complexes (i.e., state II) are poorly understood. To better understand this mechanism, we employed coarse‐grained molecular dynamics (CGMD) simulations of pHLIP interacting with either 1‐palmitoyl‐2‐oleoyl‐ sn ‐3‐phosphocholine (POPC) or mixed POPC:1‐palmitoyl‐2‐oleoyl‐3‐ sn ‐phosphoserine (POPS) lipid bilayers to determine the effect of headgroup charge on the ability of pHLIP to bind to a membrane surface. Our goal was to rigorously determine the kinetics of binding between pHLIP and the bilayer and to identify the key biophysical interactions that lead to a stable binding event, as well as characterizing the effect of headgroup composition on these behaviors. Our preliminary results show that the interaction of pHLIP with a POPC bilayer initiates at the N‐terminus and induces partial helicity. As the concentration of the anionic POPS lipids increases, the interactions between the anionic residues of pHLIP in the C‐terminus and the charged lipid head groups will be less favorable due electrostatic repulsions. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .