Computational protocol: Molecular Dynamics Simulations of the Permeation of Bisphenol A and Pore Formation in a Lipid Membrane

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Protocol publication

[…] Molecular dynamics (MD) simulations were performed on the hydrated DPPC bilayer with BPAs. The fully hydrated bilayer, composed of 128 DPPC lipids and 5800 water molecules, was developed by Tieleman and Berendsen. The force field parameters for DPPC lipids were taken from Berger et al.. The geometry of BPA was optimized by density functional theory (DFT) method at the B3LYP/6-31G (d, p) level. The topology of BPA was created by PRODRG server. However, the partial charges assigned by PRODRG were found to result in wrong water solubility and unrealistic partitioning between water and membrane. We therefore resorted to Mulliken partial charges obtained after DFT calculations, which were compatible with Berger lipid force field.All MD simulations were carried out under the isothermal-isobaric (NPT) ensemble using the Gromacs package 4.5.5 and GROMOS53a6 force field. Periodic boundary conditions were employed in all directions. The vdW interactions were treated with smooth cutoff at a distance of 12 Å, whereas the particle-mesh Ewald method was adopted to calculate the long-range electrostatic interactions. Water was represented by the SPC model. The temperature was kept stable at 323 K using the V-rescale thermostat and the pressure was controlled semi-isotropically by a Berendsen barostat. Bond lengths within BPA/DPPC and water molecules were constrained by the LINCS and the SETTLE algorithms, respectively.The free energy of BPA across the bilayer was computed from the potential of mean force (PMF) using umbrella sampling. First, we conducted steered MD simulation to pull the molecule from the aqueous phase to the middle of the membrane. Then, 30 configurations were generated along the z-axis direction (reaction coordinate). The z coordinates of COM distance between BPA and membrane in each configuration differed by about 0.1 nm. Each window was equilibrated for 5 ns and a production run of 5 ns was continued for sampling. Eventually, the PMF profile was obtained by the Weighted Histogram Analysis Method (WHAM), implemented in the GROMACS package as ‘g_wham’. The convergence and sufficiency and of each sampling were presented in the . […]

Pipeline specifications

Software tools PRODRG, GROMACS, P-LINCS
Application Drug design
Organisms Homo sapiens
Diseases Abnormalities, Drug-Induced, Neoplasms, Drug-Related Side Effects and Adverse Reactions
Chemicals 1,2-Dipalmitoylphosphatidylcholine, Hydroxyl Radical