GxxxG Motif Stabilize Ion-Channel like Pores through C&alpha;&#8213;H&middot;&middot;&middot;O Interaction in A&beta; (1-40)

Carola Rando; Giuseppe Grasso; Dibakar Sarkar; Michele Francesco Maria Sciacca; Lorena Maria Cucci; Alessia Cosentino; Giuseppe Forte; Martina Pannuzzo; Cristina Satriano; Anirban Bhunia; Carmelo La Rosa

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

2023

A&beta: (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 C&alpha:&#8213:H&middot:&middot:&middot: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&minus:1 was attributed to the interaction between Gly 7 of an alpha-helix and Asp 23 of a vicinal alpha-helix.

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