Atomistic-level study of the interactions between hIAPP protofibrils and membranes: Influence of pH and lipid composition

Abstract

The pathology of type 2 diabetes mellitus is associated with the aggregation of human islet amyloid polypeptide (hIAPP) and aggregation-mediated membrane disruption. The interactions of hIAPP aggregates with lipid membrane, as well as the effects of pH and lipid composition at the atomic level, remain elusive. Herein, using molecular dynamics simulations, we investigate the interactions of hIAPP protofibrillar oligomers with lipids, and the membrane perturbation that they induce, when they are partially inserted in an anionic dipalmitoyl-phosphatidylglycerol (DPPG) membrane or a mixed dipalmitoyl-phosphatidylcholine (DPPC)/DPPG (7:3) lipid bilayer under acidic/neutral pH conditions. We observed that the tilt angles and insertion depths of the hIAPP protofibril are strongly correlated with the pH and lipid composition. At neutral pH, the tilt angle and insertion depth of hIAPP protofibrils at a DPPG bilayer reach ~52° and ~1.62 nm with respect to the membrane surface, while they become ~77° and ~1.75 nm at a mixed DPPC/DPPG membrane. The calculated tilt angle of hIAPP at DPPG membrane is consistent with a recent chiral sum frequency generation spectroscopic study. The acidic pH induces a smaller tilt angle of ~40° and a shallower insertion depth (~1.24 nm) of hIAPP at the DPPG membrane surface, mainly due to protonation of His18 near the turn region. These differences mainly result from a combination of distinct electrostatic, van der Waals, hydrogen bonding and salt-bridge interactions between hIAPP and lipid bilayers. The hIAPP-membrane interaction energy analysis reveals that besides charged residues K1, R11 and H18, aromatic residues Phe15 and Phe23 also exhibit strong interactions with lipid bilayers, revealing the crucial role of aromatic residues in stabilizing the membrane-bound hIAPP protofibrils. hIAPP-membrane interactions disturb the lipid ordering and the local bilayer thickness around the peptides. Our results provide atomic-level information of membrane interaction of hIAPP protofibrils, revealing pH-dependent and membrane-modulated hIAPP aggregation at the early stage.

Structural Influence and Interactive Binding Behavior of Dopamine and Norepinephrine on the Greek-Key-Like Core of α-Synuclein Protofibril Revealed by Molecular Dynamics Simulations

“…Here, a contact was defined if the distance between the heavy atoms of DA/NE molecule and αS tetramer lied within 0.54 nm [65,68]. All the representations of the simulated systems were drawn with the VMD program [69].…”

“…Previous studies reported that an ion pair can be defined as a salt bridge if the centroids of the side-chain charged-group atoms in the residues (Asp or Glu with Arg, Lys, or His) lie within 4.0 Å of each other, and at least one pair of Asp or Glu side-chain carbonyl oxygen and side-chain nitrogen atom of Arg, Lys, or His is also within this distance [61][62][63]. This criterion has been widely used in many computational studies [64][65][66][67]. Therefore, in this work, a salt bridge was considered to be formed if the minimum distance between the nitrogen atom of side-chain NH 3…”

Tyrosine carbon dots inhibit fibrillation and toxicity of the human islet amyloid polypeptide

“…The toxic effects of hIAPP have been linked to perturbation of the cellular membrane by the peptide, specically involving its oligomeric aggregates. 46,47 As such, we also assessed the impact of the C-dots upon the interactions of hIAPP with lipid bilayers (Fig. 4B).…”

O papel de lipídios oxidados e surfactantes como promotores de agregados proteicos tipo amilóide

“…A segunda indicação (ii) de nossos experimentos também está em acordo com resultados da literatura onde se evidenciou que a formação de agregados do IAPP, na presença de lipossomos, acontece na superfície da membrana lipídica [175,180,181]. Primeiramente, há a ligação do monômero do IAPP na superfície da membrana [184], seguido do enovelamento da proteína para uma conformação rica em α hélice [175,180] (ou não [181]). Após, outros monômeros se agregam à estes primeiros e o oligômero formado passa por outra mundança de estrutura secundária rica em folhas β acarretando na formação da fibra amiloide [175,180,181].…”

“…Desta maneira, sugere-se que a membrana lipídica sirva de catalisadora do processo de nucleação do IAPP por oferecer uma superfície de ligação para os monômeros do polipeptídeo, onde o aumento da concentração local desencadearia a fibrilação [180,181]. De fato, simulações computacionais indicaram que o monômero do IAPP se liga à superfície de membranas de DPPG e DPPC:DPPG (7:3) penetrando até 1,62 nm [184].…”