Membrane Binding and Insertion of a pHLIP Peptide Studied by All-Atom Molecular Dynamics Simulations

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.

Cooperative Nonbonded Forces Control Membrane Binding of the pH-Low Insertion Peptide pHLIP

“…In this study, we have computationally modeled state II of wt-pHLIP and the variant, pHLIP-1. This is the first computational study of its kind, to our knowledge, because previous MD studies have focused on insertion of a-helical pHLIP (37,38), conformational sampling of gold nanoparticle-pHLIP conjugates (39), and pHLIP in solution (14,19). In contrast, the field of antimicrobial peptides and cell-penetrating peptides has been extensively studied by MD simulations (40)(41)(42).…”

Targeting Acidic Diseased Tissues by pH-Triggered Membrane-Associated Peptide Folding

“…• Since the insertion kinetics show timescales of ms to sec for the process (Karabadzhak et al, 2012), it is difficult to know which lipid bilayer organizational changes may accompany the insertion. Accurate dynamic modeling is problematical on this timescale, and results (Deng et al, 2013;Kong et al, 2014) should be regarded with caution. • As noted above, in a biological system having living cells in acidic diseased tissues, a pH gradient exists in the vicinity of the cell membrane: at the cell surface the pH can be around 6.0 and it increases with distance from the cell surface (Stock et al, 2007;Anderson et al, 2016;Wei et al, 2019).…”

Pristine and Hydroxylated Fullerenes Prevent the Aggregation of Human Islet Amyloid Polypeptide and Display Different Inhibitory Mechanisms

“…It is true that the protonation state of His will change along with the local environment changes. As done recently by other groups (Dupuis et al, 2009(Dupuis et al, , 2011Deng et al, 2013;Qiao et al, 2013), we neglected the pKa shift in all of our simulations as the involvement of pKa calculation in MD simulations makes it very computationally expensive. Every hIAPP dimer was put in the center of a cubic box with a side length of 6.7 nm.…”