{
  "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.",
  "abstract_shown": true,
  "affiliations": [
    "Unité de Recherche Microbes Evolution Phylogeny and Infections (MEPHI), IHU Méditerranée Infection, Aix-Marseille University (AMU), 13005 Marseille, France",
    "AmyPore, 13240 Septèmes-les-Vallons, France"
  ],
  "article_type": "review article",
  "arxiv": null,
  "author_total": 5,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Jacques Fantini",
      "orcid": "0000-0001-8653-5521"
    },
    {
      "affs": [
        1
      ],
      "name": "Marine Lefebvre"
    },
    {
      "affs": [
        1
      ],
      "name": "Anaïs Aulas"
    },
    {
      "affs": [
        0
      ],
      "name": "Henri Chahinian",
      "orcid": "0000-0002-9516-4168"
    },
    {
      "affs": [
        0
      ],
      "name": "Nouara Yahi"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/0fkynwc2hzj94.bib",
  "cited_by": 0,
  "doi": "10.3390/molecules31203662",
  "fulltext_url": "https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13707594/?tool=EBI",
  "id": "0fkynwc2hzj94",
  "issns": [
    "1420-3049"
  ],
  "landing_url": "https://www.mdpi.com/1420-3049/31/20/3662",
  "language": "eng",
  "licence": "CC-BY-4.0",
  "licence_label": "CC BY 4.0",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "1312|Protein Structure and Dynamics"
    ]
  ],
  "openalex": "W7221630225",
  "pdf_url": "https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13707594/pdf/?tool=EBI",
  "pmcid": "PMC13707594",
  "pmid": null,
  "published": "2026-10-01",
  "publisher": "MDPI AG",
  "ris": "https://research.draconitic.com/paper/0fkynwc2hzj94.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:18:42Z",
      "native_id": "10.3390/molecules31203662",
      "source": "crossref",
      "url": "https://www.mdpi.com/1420-3049/31/20/3662"
    },
    {
      "first_seen": "2026-10-30T12:21:49Z",
      "native_id": "PMC:PMC13707594",
      "source": "europepmc",
      "url": "https://europepmc.org/article/PMC/PMC13707594"
    }
  ],
  "subjects": [
    {
      "field": "biochemistry",
      "origin": "openalex:1312|Protein Structure and Dynamics",
      "subfield": "molecular-biology"
    }
  ],
  "title": "The Disordome Paradigm: How Intrinsic Disorder Encodes Emergent Biological Function",
  "title_text": "The Disordome Paradigm: How Intrinsic Disorder Encodes Emergent Biological Function",
  "type": "peer-reviewed",
  "updated_at": "2026-10-30T12:21:49Z",
  "url": "https://research.draconitic.com/paper/0fkynwc2hzj94",
  "venue": "Molecules",
  "versions": []
}