The Enigmatic Conserved Q134-F135-N137 Triad in SARS-CoV-2 Spike Protein: A Conformational Transducer?
et al., Biomolecules, doi:10.3390/biom16010111, Jan 2026
Computational and structural study of the SARS-CoV-2 spike protein identifying a conserved amino acid triad (Q134-F135-N137) that remains unchanged across variants despite extensive mutations in surrounding regions. The study proposes this triad initiates conformational changes in the spike protein after binding to host cell gangliosides, leading to exposure of the receptor-binding domain necessary for viral entry. Using molecular modeling, authors identify a pathway of amino acids that could transmit conformational changes from the triad through the protein structure. They suggest this conserved region could serve as a therapeutic target since it appears essential for viral function yet resistant to mutation.
Lefebvre et al., 8 Jan 2026, France, peer-reviewed, 4 authors.
Contact: jacques.fantini@univ-amu.fr (corresponding author), marine.lefebvre@etu.univ-amu.fr, nouara.yahi@univ-amu.fr.
In silico studies are an important part of preclinical research, however results may be very different in vivo.
The Enigmatic Conserved Q134-F135-N137 Triad in SARS-CoV-2 Spike Protein: A Conformational Transducer?
Biomolecules, doi:10.3390/biom16010111
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 gangliosideinduced 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.
Author Contributions: Conceptualization, J.F.; methodology, J.F., M.L., N.Y. and H.C.; validation, J.F., N.Y. and H.C.; draft preparation, J.F. and M.L.; writing-review and editing, J.F.; visualization, M.L.; supervision, J.F.; project administration, J.F. All authors have read and agreed to the published version of the manuscript.
Conflicts of Interest: The authors declare no conflict of interest.
Abbreviations The following abbreviations are used in this manuscript:
ACE-2 Angiotensin
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"abstract": "<jats:p>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.</jats:p>",
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