Affinity comparison of different THCA synthase to CBGA using modeling computational approaches.

Area of Science:

• Biochemistry
• Structural Biology
• Computational Chemistry

Background:

• Tetrahydrocannabinolic acid (THCA) is a key compound in Cannabis Sativa.
• THCA is synthesized by THCA synthase, which converts cannabigerolic acid (CBGA).
• Understanding THCA synthase structure is crucial for elucidating THCA production pathways.

Purpose of the Study:

• To generate and validate three-dimensional (3D) models of the THCA synthase protein.
• To investigate the interaction between CBGA and THCA synthase using computational docking.
• To explore the correlation between enzyme-ligand binding energy and THCA production levels in Cannabis Sativa.

Main Methods:

• Homology modeling using MODELLER v9.11 and the THCA synthase X-ray structure (PDB code 3VTE).
• Validation of 3D models using Procheck, Errat, and Verify 3D tools.
• Computational docking of CBGA to the THCA synthase active site to calculate interaction energies.

Main Results:

• Six reliable 3D models of THCA synthase were generated with high structural integrity (RMSD values between 0.290 Å-1.252 Å).
• Docking analysis successfully identified the active site pocket and revealed distinct interaction energies for CBGA in different Cannabis Sativa varieties ('fiber' vs. 'drug' types).
• Interaction energies ranged from -4.195 to -7.16 kcal/mol, suggesting a role in determining THCA levels.

Conclusions:

• The study provides accurate 3D models of THCA synthase, facilitating further structural and functional analysis.
• Computational docking indicates that CBGA-THCA synthase interaction energy is a potential determinant of THCA production in Cannabis Sativa.
• An experimental design is proposed to validate the link between enzyme affinity and THCA levels, opening avenues for future research.