PMC:7441777 / 13861-16786 JSONTXT

{"target":"https://pubannotation.org/docs/sourcedb/PMC/sourceid/7441777","sourcedb":"PMC","sourceid":"7441777","source_url":"https://www.ncbi.nlm.nih.gov/pmc/7441777","text":"2.2. Molecular dynamics simulations\nAll-atom molecular dynamics (MD) simulations were performed on the best eight selected plant-derived natural polyphenols obtained from the molecular docking study along with remdesivir, a well-known RdRp inhibitor, for studying thermodynamic stability of the docked structure. The pmemd.cuda module in AMBER18 (Case et al. 2018) was used for conducting MD simulations, and all simulations were performed utilizing the graphics card, RTX 2080Ti. We adopted the same protocol that was used in our earlier studies (Jonniya et al., 2019; Sk, Roy, Jonniya, et al., 2020; Sk, Roy, \u0026 Kar, 2020). The receptor and small molecules were described by the Amber ff14SB (Maier et al., 2015) and GAFF2 (Wang et al., 2004) force field, respectively. Ligands were assigned the AM1-BCC (Jakalian et al., 2002) atomic charges calculated using the antechamber (Wang et al., 2001) module. The complexes were then solvated using an explicit TIP3P (Price \u0026 Brooks III, 2004) water model, and nearly 38124 water molecules were needed to solvate each system. Subsequently, all solvated systems were neutralized by adding an appropriate number of Na+ ion. All bond lengths, including hydrogen atoms, were constrained by the SHAKE algorithm (Kräutler et al., 2001). This allows the usage of a 2 fs time-step. The non-bonded cut-off was set to 8 Å and the long range electrostatic interactions were evaluated using the particle-mesh Ewald (PME) (Darden et al., 1993) method. The temperature was kept at 300 K using the Langevin thermostat (Loncharich et al., 1992) with a collision frequency of 2 ps−1. The system pressure was controlled by Berendsen’s Barostat (Berendsen et al., 1984) and fixed at 1.0 bar. We used a time-step of 2.0 fs for all simulations.\nBriefly, we used two stages of minimization. Firstly, each complex was optimized by 500 steps of steepest descent followed by another 500 steps of conjugate gradient minimization, keeping all atoms of the complex restrained to their initial coordinate with a weak harmonic potential (force constant 2.0 kcal mol−1 Å−2). The second stage of minimization was carried out without any restraints by performing 100 steps of steepest descent, followed by another 900 steps of conjugate gradient minimization to remove any residual steric clashes. Subsequently, all systems were gradually heated from 0 K to 300 K at the NVT ensemble with a force constant of 2.0 kcal mol−1Å−2 acting on all solute atoms. Next, 1.0 ns equilibration MD phase was carried out without any restraint. Finally, we performed 150 ns production simulations for all four systems at the NPT ensemble. Overall, we accumulated 15000 conformations for each simulation, and we used 500 snapshots from the last 50 ns trajectories for binding affinity estimation using the MM-PBSA scheme. The trajectory analysis was done by the AmberTools19 CPPTRAJ (Roe \u0026 Cheatham III, 2013) module of 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