Abstract
Recent experiments in function mechanism study reported that a pH low-insertion peptide (pHLIP) can insert into a zwitterionic palmitoyloleoylphosphatidylcholine (POPC) lipid bilayer at acidic pH while binding to the bilayer surface at basic pH. However, the atomic details of the pH-dependent interaction of pHLIP with a POPC bilayer are not well understood. In this study, we investigate the detailed interactions of pHLIP with a POPC bilayer at acidic and basic pH conditions as those used in function mechanism study, using all-atom molecular dynamics (MD) simulations. Simulations have been performed by employing the initial configurations, where pHLIP is placed in aqueous solution, parallel to bilayer surface (system S), partially-inserted (system P), or fully-inserted (system F) in POPC bilayers. On the basis of multiple 200-ns MD simulations, we found (1) pHLIP in system S can spontaneously insert into a POPC bilayer at acidic pH, while binding to the membrane surface at basic pH; (2) pHLIP in system P can insert deep into a POPC bilayer at acidic pH, while it has a tendency to exit, and stays at bilayer surface at basic pH; (3) pHLIP in system F keeps in an α-helical structure at acidic pH while partially unfolding at basic pH. This study provides at atomic-level the pH-induced insertion of pHLIP into POPC bilayer.
Highlights
The pH low-insertion peptides have received significant attention in recent years due to their ability to target acidic tissues and selectively translocate polar, cell-impermeable molecules across cell membranes [1,2]
The peptide at basic pH is more hydrophilic, energetically more favorable to bind to hydrophilic headgroups of POPC bilayer, whereas the pH low-insertion peptide (pHLIP) at acidic pH is more hydrophobic, energetically more favorable to stay inside the hydrophobic tail region of POPC bilayer
We have investigated the detailed interactions of pHLIP with POPC bilayers at acidic and basic pH conditions by performing six 200-ns all-atom molecular dynamics (MD) simulations starting from three different configurations
Summary
The pH low-insertion peptides (pHLIPs) have received significant attention in recent years due to their ability to target acidic tissues and selectively translocate polar, cell-impermeable molecules across cell membranes [1,2]. Due to its small size, pHLIP serves as a model peptide for studying membrane protein folding and bilayer insertion. Unlike other membrane active peptides [9], pHLIP helices cause minimal disturbance to phospholipid bilayers: Namely, they do not induce membrane leakage [1,6,10]. Owing to this exceptional property, many technologies have been developed for targeting, imaging, and drug molecule delivery using pHLIP [7,8,11,12,13,14]
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