HIV-1 integrase catalytic core: molecular dynamics and simulated fluorescence decays

Area of Science:

• Biophysics
• Structural Biology
• Computational Chemistry

Background:

• HIV-1 integrase is a crucial enzyme for viral replication.
• Understanding its catalytic core dynamics is key to developing inhibitors.
• Previous studies lacked detailed dynamic information under varying conditions.

Purpose of the Study:

• To investigate the conformational dynamics of the HIV-1 integrase catalytic core using molecular dynamics simulations.
• To correlate simulated dynamics with experimental fluorescence data.
• To explore the influence of divalent cations and temperature on integrase structure.

Main Methods:

• Two molecular dynamics simulations of the HIV-1 integrase catalytic core were performed.
• Simulations were conducted in the absence and presence of Mg(2+).
• Fluorescence intensity and anisotropy decays were computed and compared to experimental data.

Main Results:

• In the absence of Mg(2+), the catalytic core adopted two main conformations with a transition around 3.4 ns.
• In the presence of Mg(2+), the structure remained stable.
• Simulated fluorescence intensity decays showed excellent agreement with experimental data at both 5°C and 30°C.
• Simulated fluorescence anisotropy decays fit experimental data excellently at 5°C but poorly at 30°C.

Conclusions:

• Divalent cations stabilize the HIV-1 integrase catalytic core conformation.
• Temperature significantly affects the dynamics of the integrase, particularly internal motions.
• The observed discrepancies at 30°C may indicate dimerization or increased uncorrelated internal motions.