Session: 17-15-01: Society-Wide Micro/Nano Poster Forum

Paper Number: 99131

99131 - A Steered Molecular Dynamics Study of Unbinding of Ritonavir and Xk263 From Hiv-1 Protein Binding Pocket 

Protein-ligand interactions play an important role in a wide range of physiological processes especially when it comes to developing new drugs or providing targeted drug delivery. Human Immunodeficiency Virus-1 (HIV-1) protease shows a unique phenomenon of viral replication that makes it one of the most prominent targets for therapy against AIDS. To design new and effective inhibitors that can neutralize the active site of the HIV-1 protease, it is important to get a further understanding of the mechanisms by which some of the existing inhibitors unbind from the protease under specified conditions. In this work, the unbinding of two of the potent inhibitors, Ritonavir and XK263 molecule from the binding pocket of the HIV-1 protein dimer has been investigated using all-atom steered molecular dynamics (SMD) simulation with an explicit solvent model and binding free energy (ΔG_binding) calculations based on umbrella sampling (US) technique. We performed the molecular dynamics simulation with the commercially available GROMACS package using the CHARMM36 all-atom force field applied to both the ligands and the protease dimer. Initially, the crystal structures of the docked protein-ligand complex pdb files are used to perform the steered molecular dynamics (SMD) simulations for a period of 500 picoseconds (ps) to perform the calculations for temporal variation of average unbinding force and center of mass displacement of the corresponding ligands. During the SMD simulations, we used an external stimulus with a harmonic force constant of 1000 kJ.mol^-1.nm^-2 and a pulling rate of 0.01 nm/ps. The umbrella sampling technique has been used to generate a number of sample trajectory configurations after the SMD simulation to evaluate the potential of mean force (PMF) along the protein-ligand reaction coordinates considering a 0.2 nm of spacing between each of them. Weighted Histogram Analysis Method (WHAM) is used to calculate PMF which ultimately leads to the calculations of the respective binding free energies. Our results showed that the Ritonavir molecule showed better binding strength in terms of staying attached to the HIV-1 protease binding pocket for 40-50 picoseconds longer than the XK263 molecule during the SMD simulation and the corresponding maximum pulling force required to unbind XK263 is 350 kJ/mol.nm less than that for the Ritonavir. Binding free energy calculations agree perfectly with this finding, where ΔG_binding for Ritonavir (~22.0 kcal/mol) is almost 4 times as much as for the XK263 (~5.5 kcal/mol). The temporal change of the corresponding protein-ligand interaction energies (Coulombic and Lennard-Jones) and calculations for hydrogen bond formation also satisfy our earlier results. The results of this work can lead us to an understanding of how these two ligands can be a potential drug candidate for the HIV-1 virus and also show the way for other potential HIV-1 protease inhibitors in the future.

Presenting Author: Mohammad Akram Lehigh University

Presenting Author Biography: I am a Graduate Research Assistant in Mechanical Engineering and Mechanics at Lehigh University. I have completed my Bachelors of Engineering in 2021 from Jadavpur University, Kolkata, India.

Authors:

Mohammad Akram Lehigh University
Tanumoy Banerjee Lehigh University
Ganesh Balasubramanian Lehigh University