Computational protocol: Structure–activity exploration of a small-molecule Lipid II inhibitor

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Protocol publication

[…] Molecular modeling, energy minimization, and MD simulations were performed with the program CHARMM using the CHARMM36 lipid and protein force field, for Lipid II and the TIP3P water model along with the CHARMM General force field– for the ligands. Using the final snapshot from previously published 10 ns MD simulations of the BAS00127538–Lipid II complex in aqueous solution, the aromatic rings of the Steven Fletcher (SF) analogs were aligned with those of BAS00127538. Each system was then subjected to a short energy minimization following which a 100 ps MD simulation with a short time step of 0.5 fs was carried out. Each system was then subjected to a 20 ns MD simulation run with a time step of 1 fs. Simulations were carried out in the NPT ensemble at 300 K and 1 atm with SHAKE of covalent bonds involving hydrogens, and there were no restraints in the simulations. Free energies of binding, ΔG, were estimated using the linear interaction energy method as follows: ΔG=α(〈Eboundelec〉−〈Eunboundelec〉)+β(〈Eboundvdw〉−〈Eunboundvdw〉)+γ(1)where α =0.5, β =0.16, γ cancels out as we only considered the relative free energies ΔΔG, and the unbound interaction energies were computed from 5 ns MD simulations of the compounds alone in water. […]

Pipeline specifications

Software tools CHARMM, CGenFF
Application Membrane protein analysis