GxxxG Motif Stabilize Ion-Channel like Pores through Cα-H···O Interaction in Aβ (1-40)

Int J Mol Sci. 2023 Jan 22;24(3):2192. doi: 10.3390/ijms24032192.

Abstract

Aβ (1-40) can transfer from the aqueous phase to the bilayer and thus form stable ion-channel-like pores where the protein has alpha-helical conformation. The stability of the pores is due to the presence of the GXXXG motif. It has been reported that these ion-channel-like pores are stabilized by a Cα-H···O hydrogen bond that is established between a glycine of the GXXXG sequence of an alpha-helix and another amino acid of a vicinal alpha-helix. However, conflicting data are reported in the literature. Some authors have suggested that hydrogen bonding does not have a stabilizing function. Here we synthesized pentapeptides having a GXXXG motif to explore its role in pore stability. We used molecular dynamics simulations, quantum mechanics, and experimental biophysical techniques to determine whether hydrogen bonding was formed and had a stabilizing function in ion-channel-like structures. Starting from our previous molecular dynamics data, molecular quantum mechanics simulations, and ATR data showed that a stable ion-channel-like pore formed and a band centered at 2910 cm-1 was attributed to the interaction between Gly 7 of an alpha-helix and Asp 23 of a vicinal alpha-helix.

Keywords: AFM; Aβ; FTIR-ATR; hydrogen bond; ion-channel-like; membrane; pore; quantum mechanics; toxicity.

MeSH terms

  • Amino Acids*
  • Amyloid beta-Peptides / chemistry
  • Glycine / chemistry
  • Hydrogen Bonding
  • Ion Channels*
  • Molecular Conformation
  • Molecular Dynamics Simulation

Substances

  • Amino Acids
  • Glycine
  • Ion Channels
  • Amyloid beta-Peptides

Grants and funding

This article was partially supported by the University of Catania grant “PiaCeri linea di intervento 2”. This work was also partly supported by Department of Biotechnology (BT/PR29978/MED/30/2037/2018 to AB) Govt. of India and partly by Bose Institute intramural extramural research fund (R/16/19/1615 to AB). University of Catania, Italy. Bose Institute, India.