# The Enigmatic Conserved Q134-F135-N137 Triad in SARS-CoV-2 Spike Protein: A Conformational Transducer?

## TL;DR

This paper explores how a specific amino acid triad in the SARS-CoV-2 spike protein may control a conformational change that enables viral entry into cells.

## Contribution

The study proposes that the conserved Q134-F135-N137 triad acts as a conformational transducer in the spike protein's N-terminal domain.

## Key findings

- The Q134-F135-N137 triad is conserved and may transmit conformational changes triggered by gangliosides.
- A chain of aromatic residues in the N-terminal domain may control electron transfer, suggesting a dual conformational/quantum wave.
- The triad represents a stable target for therapies to disrupt viral entry despite N-terminal domain variability.

## Abstract

Lipid raft-associated gangliosides facilitate the early stages of SARS-CoV-2 entry by triggering the exposure of the receptor-binding domain (RBD) within the trimeric spike protein, which is initially sequestered. A broad range of in silico, cryoelectron microscopy and physicochemical approaches indicate that the RBD becomes accessible after a ganglioside-induced conformational rearrangement originating in the N-terminal domain (NTD) of one protomer and propagating to the neighboring RBD. We previously identified a triad of amino acids, Q134-F135-N137, as a strictly conserved element on the NTD. In the present review, we integrate a series of structural and experimental data revealing that this triad may act as a conformational transducer connected to a chain of residues that are capable of transmitting an internal conformational wave within the NTD. This wave is generated at the triad level after physical interactions with lipid raft gangliosides of the host cell membrane. It propagates inside the NTD and collides with the RBD of a neighboring protomer, triggering its unmasking. We also identify a chain of aromatic residues that are capable of controlling electron transfer through the NTD, leading us to hypothesize the existence of a dual conformational/quantum wave. In conclusion, the complete conservation of the Q134-F135-N137 triad despite six years of extensive NTD remodeling underscores its critical role in the viral life cycle. This triad represents a potential Achilles’ heel within the hyper-variable NTD, offering a stable target for therapeutic or vaccinal interventions to disrupt the conformational wave and prevent infection. These possibilities are discussed.