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Enhanced and Classical MD Simulations Map Aggregation-Prone Regions in the Olfactomedin Domain of Myocilin

Inci Sardag1, Zeynep Sevval Duvenci2, Emel Timucin3

  • 1Department of Molecular Biology and Genetics, Bogazici University, Istanbul 34342, Turkey.

Journal of Chemical Information and Modeling
|December 24, 2025
PubMed

Insights

Researchers mapped aggregation-prone regions in myocilin's olfactomedin domain. These regions, rich in hydrophobic residues, are key to protein aggregation and potential therapeutic targets for preventing disease.

Area of Science:

  • Biophysics
  • Computational Biology
  • Structural Biology

Background:

  • Myocilin aggregation is implicated in certain diseases.
  • The olfactomedin (OLF) domain is crucial for myocilin function and aggregation.
  • Understanding aggregation-prone regions (APRs) is vital for therapeutic development.

Purpose of the Study:

  • To computationally map the aggregation-prone regions (APRs) within the human myocilin olfactomedin (OLF) domain.
  • To identify specific molecular interfaces and residue characteristics contributing to OLF aggregation.
  • To explore the potential of identified APRs as therapeutic targets.

Main Methods:

  • Utilized extensive molecular dynamics (MD) simulations (21 μs total) including classical MD, Gaussian-accelerated MD, and chemical denaturant simulations.
  • Employed two structure-based aggregation propensity predictors to identify potential APRs.
  • Analyzed changes in residue solvent exposure and surface electrostatics in MD conformations compared to the crystal structure.

Main Results:

  • Identified five APRs (residues 246-260, 276-283, 301-317, 364-379, 430-451) enriched in hydrophobic/aromatic residues.
  • Confirmed an experimentally identified amyloidogenic peptide (residues 430-451) as an APR.
  • Found that blade A interfaces (AB and AE) were critical for destabilization, linked to APRs 276-283 and 301-317.
  • Observed consistent solvent exposure of aromatic/hydrophobic residues in APRs during simulations, suggesting upstream involvement in aggregation.

Conclusions:

  • The study provides a detailed computational map of OLF aggregation hotspots.
  • Destabilization of specific interfaces and exposure of APRs are key events preceding OLF aggregation.
  • The identified APRs represent promising therapeutic targets for preventing myocilin aggregation and associated pathologies.

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