Conserved water molecules shape the pathogenicity of missense variants in human proteins
Clicks: 10
ID: 327177
2026
Article Quality & Performance Metrics
Overall Quality
Not rated
Combines reader engagement with the AI quality analysis. This
article has not been analysed, so there is no overall score —
reader engagement is measured and shown alongside.
Reader Engagement
Emerging Content
2.7
/100
10 views
9 readers
AI Quality Assessment
Not analyzed
Readership in this journal
EmergingRanked #140 of 253 articles by views in molecular biology and evolution
Most read
Least read
Bar heights use a square-root scale. Only the 120 most-read articles are drawn; the journal has 253 in total.
Mint this article as an NFT
Not yet mintedCreate a permanent, verifiable on-chain record of this article on the Scimatic Network. The NFT is held in your Journament account, and you can withdraw it to your own wallet at any time.
5
SUSD
one-off · no wallet required
Abstract
Conserved water molecules (CWMs) are tightly bound solvent molecules that occupy well-defined, recurrent positions in protein structures. Although they are known to influence protein stability, function, and ligand binding, their role in shaping the effects of human missense variants remains largely unexplored. Here, we demonstrate that CWMs are a previously underappreciated determinant of missense variant pathogenicity. By predicting ligand-binding and CWM sites across human PDB structures and mapping missense variants to these sites and the remaining protein surface, we found that pathogenic variants were significantly enriched at CWM sites, whether overlapping or outside other ligand-binding regions. This enrichment exceeded that observed for binding sites as a whole, indicating a broader role for water-mediated interactions in modulating variant effects. To explore a mechanistic basis for this association, we performed molecular dynamics simulations of human lysosomal acid glucosylceramidase (GCase), encoded by GBA1 and implicated in Gaucher disease and Parkinson's disease risk. Selective destabilization of a CWM site in wild-type GCase produced structural and dynamical changes resembling those observed in the pathogenic L444P variant, whereas stabilization of this site in L444P shifted several measures toward wild-type behavior. These results suggest that disruption of a single CWM can contribute to long-range structural remodeling observed in a disease-associated variant. Together, our findings identify CWMs as a novel structural constraint shaping the distribution and effects of pathogenic missense variants. Incorporating water-mediated interactions into structural models provides a generalizable framework for interpreting human genetic variation and its contribution to disease.
| Reference Key |
openalex_W7204826452
Use this key to autocite in the manuscript while using
SciMatic Manuscript Manager or Thesis Manager
|
|---|---|
| Authors | Janez Konc, Karmen Recer, Tanja Kunej, Dušanka Janežič |
| Journal | molecular biology and evolution |
| Year | 2026 |
| DOI |
10.1093/molbev/msag217
|
| URL | |
| Keywords | Keywords not found |
Citations
No citations found. To add a citation, contact the admin at info@scimatic.org
Comments
No comments yet. Be the first to comment on this article.