Binding Interaction Between Two Mutant Myocilin Olfactomedin Domain Monomers in a Homodimer

Area of Science:

• Structural biology
• Glaucoma pathogenesis
• Protein aggregation

Background:

• Myocilin-associated glaucoma involves mutations in the olfactomedin domain (mOLF) of myocilin, leading to protein aggregation.
• mOLF-mOLF dimerization is a suspected initial step in myocilin aggregation, but molecular details are lacking.
• Understanding these interactions is crucial for elucidating glaucoma mechanisms.

Purpose of the Study:

• To investigate the molecular interactions governing mOLF-mOLF homodimer formation in the I477N mutant.
• To identify key residues and interaction types mediating this dimerization.
• To provide insights into the early stages of myocilin aggregation.

Main Methods:

• High-quality structure prediction of I477N mutant mOLF using AlphaFold2.
• Molecular docking and molecular dynamics simulations to model the I477N mOLF-mOLF homodimer.
• Molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) with per-residue energy decomposition.

Main Results:

• A stable I477N mOLF-mOLF homodimer model was successfully generated.
• Key binding interactions include hydrogen bonds, salt bridges, and van der Waals forces.
• Residues Asp395 and Arg681 were identified as critical for initial mOLF-mOLF dimerization.

Conclusions:

• The study provides a molecular-level understanding of I477N mOLF homodimerization.
• This dimerization, mediated by specific residues, represents a potential initial step in myocilin aggregation.
• Further aggregation may involve previously identified peptides (P1 and P3), suggesting a multi-step process.