DOI: 10.6084/m9.figshare.25827547
title: Akt1 prodigiosin docking and dynamic molecular

description: <b>Molecular docking </b><b>dynamic simulations</b>Protein-Ligand docking was performed using Molecular Operating Environment (MOE). Preparation of 3D Structure of Ligands and Protein Targets: The 3D structures built of Akt1. The three-dimensional (3D) structure of ligands such as PG (CID 135455579), ATP (CID 5957), IQO (CID 10196499) and Akt1 inhibitor VII (PubChem ID: 10196499), as well as the inhibitor evaluated, were retrieved from the PubChem compound database. The ligand molecules obtained from PubChem were optimized using molecular mechanics with the CHARMM27 force field until reaching a gradient of 0.01 kcal/(Å.mol). The optimized structures were saved in a mdb file format and compiled into a single database. Subsequently, both the receptor and ligands underwent 3D protonation in MOE using the default procedure. The preparation process involved adding restraint tethers to atoms, annotating ligand identification, adding hydrogen atoms, and refining coordinates. Identifying potential binding sites (also known as cavities or active sites) was accomplished using MOE’s Site Finder function. To perform molecular docking, the prepared ligand database was subjected to MOE’s DOCK module. The docking process utilized Placement Triangle Matcher and London dG rescoring, generating 100 poses. These poses then underwent Induced Fit Refinement and GBVI/WSA dG scoring to select the top five binding poses for further analysis, aiming to obtain the best possible score for each ligand. Finally, the most favorable pose with the lowest energy was chosen for subsequent useMoreover, the docking poses and ligand interactions were viewed using MOE (Frikha et al., 2024).<b>Molecular dynamic simulations</b>The molecular dynamics simulation was conducted to explore the dynamic interactions between the ligand and Akt1 protein complex. Following the methodology outlined by Faker et al. 2024,(Frikha et al., 2024) Here's a breakdown of the steps outlined: (1) Preparation of Inputs: The CHARMM-GUI was used to prepare inputs with the CHARMM36 force field for molecular simulations. (2) System Setup: The initial structure was placed in a rectangular box, solvated with water molecules using the TIP3P model, and neutralized by adding potassium (K+) and chloride (Cl-) ions. (3) Energy Minimization: The system underwent energy minimization using the steepest descent energy minimization algorithm for 50,000 steps to relieve steric clashes and correct bad contacts. (4) Pre-Equilibration Simulation: A pre-equilibration simulation was conducted for 125 picoseconds (ps) in the NVT ensemble (constant number of particles, volume, and temperature) at 300 Kelvin (K) using velocity rescaling with a stochastic term. (5) NPT Equilibrium Simulation: Each system underwent an NPT equilibrium simulation for 125 ps in the NPT ensemble (constant number of particles, pressure, and temperature). The pressure was controlled at 1 bar using the C-rescale barostat. (6) Constraint Handling: The linear constraint solver (LINCS) algorithm was applied to maintain bond constraints during the simulation. (6) Periodic Boundary Conditions (PBC): PBC were employed in the x, y, and z directions to minimize edge effects and simulate an infinitely repeating system. (7) Interactions Modeling: Short-range van der Waals interactions were modeled using the Lennard-Jones (LJ) potential with a cut-off radius of 1.2 nanometers (nm). Long-range electrostatic interactions were calculated using the particle-mesh Ewald (PME) algorithm, with a real space cutoff of 1.2 nm. (8) Initial Velocities Assignment: Initial velocities of particles were assigned based on Maxwell distributions to set the system in motion. (9) Molecular Dynamics Simulation: tow simulations have been performed between 10 and 100 nanosecond (ns) with sampling of each 5 ns, MD simulation was conducted to observe and analyze the system's behavior over an extended period. (10) Analysis: Various parameters including root mean square deviations (RMSD), residue root means square fluctuation (RMSF), number of hydrogen bonds (HB), radius of gyration (Rg) were calculated to analyze the system's dynamics and interactions. This protocol provides a comprehensive approach to studying the behavior of protein-ligand complexes using MD simulations