The Mechanism Of The M-T Hook Structure In HIV-1 Fusion Inhibitor

HIV-1 membrane fusion has a big contribution in the process that HIV-1 entries host cells. In the clinical treatment of the AIDS patients, fusion inhibitors have been proposed. The fusion inhibitor approved by the FDA is T20 only. But it has some drawbacks in clinical applications, and then people developed a new generation of fusion inhibitors. But, developing a short peptide that with a high anti-HIV potency is considered with a huge challenge. He et al. found that two residues, Met626 and Thr627, located the upstream of the C-terminal heptad repeat of the gp41, formed a unique hooklike structure(M-T hook) that can dramatically improve the binding stability and antiHIV activity of the inhibitors.In this work, we explored the molecular mechanism why M-T hook structure could improve the anti-HIV activity of inhibitors. Firstly, molecular dynamic simulation methods was used to obtain information on the time evolution between gp41 and ligands. We do 50 ns molecular dynamic simulations to obtain the trajectory information of the two complexes(gp41-MT-SC22 KE, gp41-SC22EK) system. Secondly, from the simulation information, molecular mechanics Poisson-Boltzmann surface area(MM-PBSA) and molecular mechanics Generalized Born surface area(MM-GBSA) methods were used to calculate the binding free energies. The binding free energy of the ligand with M-T hook was even higher than the other without M-T. Further studies showed that the hydrophobic interactions made the dominant contribution to the binding free energy. In the decomposition of the binding free energy, we found that the van der Waals have the most contribution to the binding free energy, is the main energy to drive the inhibitor to the receptor. The numbers of Hydrogen bonds between gp41 and the ligand with M-T hook structure were more than the other.Our topic explore the mechanism of the M-T hook structure how to improve the activity and stability of short peptide fusion using molecular dynamic simulations and binding free energy calculation methods. These findings should provide a new method to explore the inhibition mechanism of the short peptide fusion inhibitors and be useful for the rational design of novel fusion inhibitors in the future.