Henri Chahinian

Classical structural biology equates function with a fixed three-dimensional fold, a view challenged by intrinsically disordered proteins (IDPs) and regions (IDRs), which populate broad conformational ensembles rather than a unique structure. This article introduces the “disordome” paradigm, extending Uversky’s “unfoldome” to describe how function emerges from electrostatic and hydration landscapes that reshape reversibly upon encounter with a partner. Using α-synuclein binding to ganglioside-enriched rafts and IDR-driven liquid–liquid phase separation, we argue that transient folding-upon-binding events, potentially entropically cheap, generate information-rich complexes and condensates that dissolve once conditions change, consistent with the second law of thermodynamics. We trace this logic to overlooked precursors: in 1957 Klotz invoked rubber elasticity to introduce entropy as the driver of protein “disorientation”, while in 1962 Bernal described such proteins as chains “coiled in different ways” and formulated a “two-atom rule” whereby bonding constraints fix atomic geometry only up to two atoms apart. We argue that the local under-determination described by this two-atom rule, left unresolved in IDPs by any conserved network of contacts, helps explain why AlphaFold fails on IDPs. A quantum-mechanical pillar (dispersion, OH–π contacts, tunneling) is proposed as underrepresented in IDP research. We discuss implications for the origin of life, cellular regulation via condensates, and a therapeutic logic (“target the target, not the arrow”) illustrated by AmyP53, which occupies raft gangliosides rather than disordered amyloid proteins in Alzheimer’s and Parkinson’s diseases.

I thank the author for this clear and well-documented review of the major historical stages of reflection on the definition of life. The narrative thread, from ancient animism to Schrödinger’s reductionism and the subsequent biological consensus, is...

Serotonergic signaling is traditionally conceived as a transient, vesicle-mediated process restricted to the synaptic cleft. Here, we propose an expanded model in which serotonin can also be inserted into the plasma membrane of neurons and glial cells, forming a stable, membrane-associated reservoir that prolongs its availability beyond classical synaptic timescales. In this framework, the synapse emerges not as a simple neurotransmitter–receptor interface but as a dynamic, multiscale medium where membrane order, hydration, and quantum-level processes jointly govern information flow. Two temporal “tunnels” appear to regulate serotonin bioavailability: its aggregation in synaptic vesicles during exocytosis, and its cholesterol-dependent insertion into neuronal and glial membranes at the tripartite synapse. Lipid raft microdomains enriched in cholesterol and gangliosides thus act as active regulators of a continuum between transient and constitutive serotonin signaling. This extended serotonergic persistence prompts a reconsideration of current pharmacological models and the action of antidepressants such as fluoxetine, which not only inhibits the serotonin transporter (SERT) but also accumulates in lipid rafts, perturbs raft organization, and alters serotonin–cholesterol equilibria, contributing to SERT-independent effects. Grounded in the recently established fundamental parameters of biological systems, this model invites a broader, quantum-informed rethinking of synaptic transmission.

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.

Most studies on the docking of ivermectin on the spike protein of SARS-CoV-2 concern the receptor binding domain (RBD) and, more precisely, the RBD interface recognized by the ACE2 receptor. The N-terminal domain (NTD), which controls the initial attachment of the virus to lipid raft gangliosides, has not received the attention it deserves. In this study, we combined molecular modeling and physicochemical approaches to analyze the mode of interaction of ivermectin with the interface of the NTD-facing lipid rafts of the host cell membrane. We characterize a binding area that presents point mutations and deletions in successive SARS-CoV-2 variants from the initial strain to omicron KP.3 circulating in many countries in 2024. We show that ivermectin has exceptional flexibility, allowing the drug to bind to the spike protein of all variants tested. The energy of interaction is specific to each variant, allowing a classification according to their affinity for ivermectin in the following ascending order: Omicron KP.3 < Delta < Omicron BA.5 < Alpha < Wuhan (B.1) < Omicron BA.1. The binding site of ivermectin is subject to important variations of the NTD, including the Y144 deletion. It overlaps with the ganglioside binding domain of the NTD, as demonstrated by docking and physicochemical studies. These results suggest a new mechanism of antiviral action for ivermectin based on competitive inhibition for initial virus attachment to lipid rafts. The current KP.3 variant is still recognized by ivermectin, although with an affinity slightly lower than the Wuhan strain.

Serotonin is distinct among synaptic neurotransmitters because it is amphipathic and released from synaptic vesicles at concentrations superior to its water solubility limit (270 mM in synaptic vesicles for a solubility limit of 110 mM). Hence, serotonin is mostly aggregated in the synaptic cleft, due to extensive aromatic stacking. This important characteristic has received scant attention, as most representations of the serotonergic synapse take as warranted that serotonin molecules are present as monomers after synaptic vesicle exocytosis. Using a combination of in silico and physicochemical approaches and a new experimental device mimicking synaptic conditions, we show that serotonin aggregates are efficiently dissolved by gangliosides (especially GM1) present in postsynaptic membranes. This initial interaction, driven by electrostatic forces, attracts serotonin from insoluble aggregates and resolves micelles into monomers. Serotonin also interacts with cholesterol via a set of CH-π and van der Waals interactions. Thus, gangliosides and cholesterol act together as a functional serotonin-collecting funnel on brain cell membranes. Based on this unique mode of interaction with postsynaptic membranes, we propose a new model of serotonergic transmission that takes into account the post-exocytosis solubilizing effect of gangliosides and cholesterol on serotonin aggregates.

The synapse is a piece of information transfer machinery replacing the electrical conduction of nerve impulses at the end of the neuron. Like many biological mechanisms, its functioning is heavily affected by time constraints. The solution selected by evolution is based on chemical communication that, in theory, cannot compete with the speed of nerve conduction. Nevertheless, biochemical and biophysical compensation mechanisms mitigate this intrinsic weakness: (i) through the high concentrations of neurotransmitters inside the synaptic vesicles; (ii) through the concentration of neurotransmitter receptors in lipid rafts, which are signaling platforms; indeed, the presence of raft lipids, such as gangliosides and cholesterol, allows a fine tuning of synaptic receptors by these lipids; (iii) through the negative electrical charges of the gangliosides, which generate an attractive (for cationic neurotransmitters, such as serotonin) or repulsive (for anionic neurotransmitters, such as glutamate) electric field. This electric field controls the flow of glutamate in the tripartite synapse involving pre- and post-synaptic neurons and the astrocyte. Changes in the expression of brain gangliosides can disrupt the functioning of the glutamatergic synapse, causing fatal diseases, such as Rett syndrome. In this review, we propose an in-depth analysis of the role of gangliosides in the glutamatergic synapse, highlighting the primordial and generally overlooked role played by the electric field of synaptic gangliosides.

Defining life is an arduous task that has puzzled philosophers and scientists for centuries. Yet biology suffers from a lack of clear definition, putting biologists in a paradoxical situation where one can describe at the atomic level complex objects that remain globally poorly defined. One could assume that such descriptions make it possible to perfectly characterize living systems. However, many cases of misinterpretation put this assumption into perspective. In this article, we focus on critical parameters such as time, water, entropy, space, quantum properties, and electrostatic potential to redefine the nature of living matter, with special emphasis on biological coding. Where does the DNA double helix come from, why cannot the reproduction of living organisms occur without mutations, what are the limitations of the genetic code, and why do not all proteins have a stable three-dimensional structure? There are so many questions that cannot be resolved without considering the aforementioned parameters. Indeed, (i) time and space constrain many biological mechanisms and impose drastic solutions on living beings (enzymes, transporters); (ii) water controls the fidelity of DNA replication and the structure/disorder balance of proteins; (iii) entropy is the driving force of many enzymatic reactions and molecular interactions; (iv) quantum mechanisms explain why a molecule as simple as hydrocyanic acid (HCN) foreshadows the helical structure of DNA, how DNA is stabilized, why mutations occur, and how the Earth magnetic field can influence the migration of birds; (v) electrostatic potential controls epigenetic mechanisms, lipid raft functions, and virus infections. We consider that raising awareness of these basic parameters is critical for better understanding what life is, and how it handles order and chaos through a combination of genetic and epigenetic mechanisms. Thus, we propose to incorporate these parameters into the definition of life.

The molecular mechanisms controlling the adaptation of viruses to host cells are generally poorly documented. An essential issue to resolve is whether host membranes, and especially lipid rafts, which are usually considered passive gateways for many enveloped viruses, also encode informational guidelines that could determine virus evolution. Due to their enrichment in gangliosides which confer an electronegative surface potential, lipid rafts impose a first control level favoring the selection of viruses with enhanced cationic areas, as illustrated by SARS-CoV-2 variants. Ganglioside clusters attract viral particles in a dynamic electrostatic funnel, the more cationic viruses of a viral population winning the race. However, electrostatic forces account for only a small part of the energy of raft-virus interaction, which depends mainly on the ability of viruses to form a network of hydrogen bonds with raft gangliosides. This fine tuning of virus-ganglioside interactions, which is essential to stabilize the virus on the host membrane, generates a second level of selection pressure driven by a typical induced-fit mechanism. Gangliosides play an active role in this process, wrapping around the virus spikes through a dynamic quicksand-like mechanism. Viruses are thus in an endless race for access to lipid rafts, and they are bound to evolve perpetually, combining speed (electrostatic potential) and precision (fine tuning of amino acids) under the selective pressure of the immune system. Deciphering the host membrane guidelines controlling virus evolution mechanisms may open new avenues for the design of innovative antivirals.

Virus-cell interactions involve fundamental parameters that need to be considered in strategies implemented to control viral outbreaks. Among these, the surface electrostatic potential can give valuable information to deal with new epidemics. In this article, we describe the role of this key parameter in the hemagglutination of red blood cells and in the co-evolution of synaptic receptors and neurotransmitters. We then establish the functional link between lipid rafts and the electrostatic potential of viruses, with special emphasis on gangliosides, which are sialic-acid-containing, electronegatively charged plasma membrane components. We describe the common features of ganglioside binding domains, which include a wide variety of structures with little sequence homology but that possess key amino acids controlling ganglioside recognition. We analyze the role of the electrostatic potential in the transmission and intra-individual evolution of HIV-1 infections, including gatekeeper and co-receptor switch mechanisms. We show how to organize the epidemic surveillance of influenza viruses by focusing on mutations affecting the hemagglutinin surface potential. We demonstrate that the electrostatic surface potential, by modulating spike-ganglioside interactions, controls the hemagglutination properties of coronaviruses (SARS-CoV-1, MERS-CoV, and SARS-CoV-2) as well as the structural dynamics of SARS-CoV-2 evolution. We relate the broad-spectrum antiviral activity of repositioned molecules to their ability to disrupt virus-raft interactions, challenging the old concept that an antibiotic or anti-parasitic cannot also be an antiviral. We propose a new concept based on the analysis of the electrostatic surface potential to develop, in real time, therapeutic and vaccine strategies adapted to each new viral epidemic.