The Disordome Paradigm: How Intrinsic Disorder Encodes Emergent Biological Function
- 1Unité de Recherche Microbes Evolution Phylogeny and Infections (MEPHI), IHU Méditerranée Infection, Aix-Marseille University (AMU), 13005 Marseille, France
- 2AmyPore, 13240 Septèmes-les-Vallons, France
Abstract
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.
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BibTeX
@article{fantini2026disordome,
title = {{The Disordome Paradigm: How Intrinsic Disorder Encodes Emergent Biological Function}},
author = {Jacques Fantini and Marine Lefebvre and Anaïs Aulas and Henri Chahinian and Nouara Yahi},
journal = {Molecules},
year = {2026},
month = oct,
doi = {10.3390/molecules31203662},
url = {https://www.mdpi.com/1420-3049/31/20/3662},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - The Disordome Paradigm: How Intrinsic Disorder Encodes Emergent Biological Function
AU - Jacques Fantini
AU - Marine Lefebvre
AU - Anaïs Aulas
AU - Henri Chahinian
AU - Nouara Yahi
PY - 2026
DA - 2026/10/01
JO - Molecules
DO - 10.3390/molecules31203662
UR - https://www.mdpi.com/1420-3049/31/20/3662
AB - 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.
SN - 1420-3049
ER -