Decoding pH-dependent structural dynamics of CHIKV nsP2 protease: insights from computational antiviral targeting

Area of Science:

• Virology
• Structural Biology
• Computational Chemistry

Background:

• Chikungunya virus (CHIKV) causes fever and its non-structural protein 2 (nsP2) is crucial for viral replication and immune evasion.
• Viral protease activity and stability are sensitive to environmental pH, impacting drug efficacy.
• CHIKV nsP2 combines RNA helicase and cysteine protease functions, making it a target for antiviral development.

Purpose of the Study:

• To investigate the impact of varying pH conditions on the structural flexibility and dynamics of the Chikungunya virus nsP2 protease.
• To evaluate how pH influences the binding interactions of CHIKV nsP2 protease with cysteine protease inhibitors E-64 and Leupeptin.

Main Methods:

• Extensive molecular dynamics (MD) simulations were performed on apo and holo forms of CHIKV nsP2 protease.
• Molecular docking was employed to assess inhibitor binding affinities under different pH conditions.
• Analysis included Root Mean Square Deviation (RMSD), Root Mean Square Fluctuation (RMSF), radius of gyration, and hydrogen bond counts.

Main Results:

• MD simulations showed pH-dependent shifts in the nsP2 active site and conformational reorganization.
• Catalytic dyad residues (Cys1013, His1083) exhibited notable shifts under varying pH.
• Inhibitor binding stability varied with pH, with significant fluctuations observed in loop and beta-strand regions.
• At pH 7 and 8, the beta2 strand converted to a loop, potentially affecting substrate recognition and activity.

Conclusions:

• In silico findings provide critical insights into the pH-dependent dynamic behavior of CHIKV nsP2 protease.
• The study suggests strategies for designing pH-resilient antiviral inhibitors effective across various physiological conditions.
• Understanding pH-induced structural changes is vital for developing robust CHIKV therapeutics.