Induced Mutation Proves a Potential Target for TB Therapy: A Molecular Dynamics Study on LprG

Area of Science:

• * Computational biophysics and structural biology.
• * Antimycobacterial drug discovery and target identification.

Background:

• * Mycobacterium tuberculosis-LprG (Mtb-LprG) is a potential target for antimycobacterial therapies.
• * Understanding the structural and dynamic impact of mutations is crucial for drug development.

Purpose of the Study:

• * To investigate the effects of the V91W mutation on Mtb-LprG stability and dynamics using molecular dynamics (MD) simulations.
• * To elucidate the role of Mtb-LprG as a potential antimycobacterial target.

Main Methods:

• * Long-range molecular dynamics (MD) simulations of wild-type and V91W mutant Mtb-LprG.
• * Post-simulation analyses including root mean square fluctuation (RMSF), dynamic cross-correlation, and principal component analysis (PCA).
• * Thermodynamic calculations and residue interaction network analysis to assess binding free energy and interactions.

Main Results:

• * The V91W mutant Mtb-LprG exhibited greater stability and flexibility compared to the wild-type.
• * MD simulations indicated increased residual flexibility and negatively correlated motions in the V91W mutant.
• * Thermodynamic analysis showed van der Waals (E_vdw) forces significantly contribute to binding free energy in the V91W mutant.

Conclusions:

• * The V91W mutation positively impacts Mtb-LprG stability and dynamics, reinforcing its potential as an antimycobacterial target.
• * This study provides a foundation for identifying novel drug targets against tuberculosis.
• * The findings support Mtb-LprG as a viable target for developing new antimycobacterial agents.