Distinct Modulation of Wild-Type and Selective Gene Mutated Vitamin D Receptor by Essential Polyunsaturated Fatty...

Area of Science:

• Biochemistry
• Molecular Biology
• Genetics

Background:

• Vitamin D deficiency is a widespread health issue.
• Mutations in the vitamin D receptor's (VDR) ligand-binding domain (LBD) can impair VDR function and lead to hormone unresponsiveness.
• Long-chain polyunsaturated fatty acids (PUFAs) are known to interact with the VDR LBD.

Purpose of the Study:

• To investigate whether PUFAs can modulate VDR dynamics and kinetics, independent of vitamin D.
• To examine the binding affinity of specific PUFAs (EPA, DHA, AA) to both wild-type and mutated VDR.

Main Methods:

• In-silico molecular docking studies to analyze the spatial arrangement and binding affinity of PUFAs in the VDR active site.
• Molecular dynamic simulations to confirm the stability of PUFA-VDR complexes, particularly DHA with mutated VDR.

Main Results:

• Docking studies revealed structure-specific binding affinities of PUFAs to VDR.
• EPA, DHA, and AA exhibited lower binding energies compared to vitamin D in wild-type VDR.
• Docosahexaenoic acid (DHA) demonstrated enhanced binding interactions with mutated VDR compared to vitamin D.

Conclusions:

• PUFAs possess unique properties for VDR activation.
• DHA shows particular promise for interacting with mutated VDR, suggesting a potential therapeutic avenue.
• These findings propose PUFAs as an alternative strategy to address vitamin D deficiency and VDR dysfunction.