{
  "abstract": "FoldX and related methods are widely used to interpret missense variants, and their sensitivity to the input structure is documented: repair of the coordinates is mandatory, averaging over structural ensembles improves agreement with experiment, and the uncertainty of a FoldX folding ΔΔG has been put at roughly ±3 kcal/mol, with binding stability worse. What has not been asked is whether that uncertainty is spread evenly over a protein. We took 258 ClinVar missense variants in glutaryl-CoA dehydrogenase, a homotetramer, verified every reference residue against the 1SIQ structure and computed ΔΔG for the 124 classified pathogenic. Eighteen variants were then recomputed on three molecular dynamics snapshots of the same complex: six interface variants selected on their monomer-to-tetramer difference, six interface variants drawn at random, and six at least 10 Å from any contact. The displacement between the crystal-based value and the relaxed-frame mean had a median of 1.10, 1.38 and 0.20 kcal/mol in the three groups (random interface against distant, Mann-Whitney p = 0.0130), while frame-to-frame scatter was indistinguishable between them (Kruskal-Wallis p = 0.385). The variation is therefore positional, and it is not explained by noise in the mean. SAAMBE-3D, a learned interface predictor, run on the same eighteen variants and the same four structures, moved by a median of 0.075 kcal/mol at the interface and by nothing at all away from it, so the instability is largely a property of FoldX. It also depends on magnitude: G171R, scored at +22.53 kcal/mol, moved 2.7%, whereas A421V moved from +0.18 kcal/mol, which reads as tolerated, to +4.37 ± 2.22. Along the way we found that ThermoMPNN given a chain selector on a tetramer returns values identical to the isolated monomer at all 7,800 scanned positions. For variant interpretation the consequence is specific: at a subunit interface, in the range where a classification is actually in doubt, a single starting structure does not support a single number.",
  "abstract_shown": true,
  "affiliations": [
    "Independent researcher",
    "Yıldız Technical University"
  ],
  "article_type": null,
  "arxiv": null,
  "author_total": 2,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Cumhur Gökhan Ekmekci"
    },
    {
      "affs": [
        1
      ],
      "name": "Ceren Aleyna Cengiz",
      "orcid": "0009-0005-2692-1865"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/aesfg1g3bctf3.bib",
  "cited_by": 0,
  "doi": "10.26434/chemrxiv.15010007/v1",
  "fulltext_url": null,
  "id": "aesfg1g3bctf3",
  "issns": [],
  "landing_url": "https://chemrxiv.org/doi/full/10.26434/chemrxiv.15010007/v1",
  "language": null,
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "journal",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "1311|Genomics and Rare Diseases"
    ]
  ],
  "openalex": "W7220858993",
  "pdf_url": "https://chemrxiv.org/doi/pdf/10.26434/chemrxiv.15010007/v1",
  "pmcid": null,
  "pmid": null,
  "published": "2026-10-06",
  "publisher": "American Chemical Society (ACS)",
  "ris": "https://research.draconitic.com/paper/aesfg1g3bctf3.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:17:22Z",
      "native_id": "10.26434/chemrxiv.15010007",
      "source": "chemrxiv",
      "url": "https://chemrxiv.org/doi/full/10.26434/chemrxiv.15010007/v3"
    }
  ],
  "subjects": [
    {
      "field": "biology",
      "origin": "openalex:1311|Genomics and Rare Diseases",
      "subfield": "genetics-genomics"
    }
  ],
  "title": "FoldX interface ΔΔG depends on which structure it starts from, and a learned predictor does not: a cautionary analysis on glutaryl-CoA dehydrogenase",
  "title_text": "FoldX interface ΔΔG depends on which structure it starts from, and a learned predictor does not: a cautionary analysis on glutaryl-CoA dehydrogenase",
  "type": "preprint",
  "updated_at": "2026-10-30T12:17:26Z",
  "url": "https://research.draconitic.com/paper/aesfg1g3bctf3",
  "venue": "ChemRxiv",
  "versions": []
}