Parametrization of macrolide antibiotics using the force field toolkit.
Macrolides are an important class of antibiotics that target the bacterial ribosome. Computer simulations of macrolides are limited as specific force field parameters have not been previously developed for them. Here, we determine CHARMM-compatible force field parameters for erythromycin, azithromycin, and telithromycin, using the force field toolkit (ffTK) plugin in VMD. Because of their large size, novel approaches for parametrizing them had to be developed. Two methods for determining partial atomic charges, from interactions with TIP3P water and from the electrostatic potential, as well as several approaches for fitting the dihedral parameters were tested. The performance of the different parameter sets was evaluated by molecular dynamics simulations of the macrolides in ribosome, with a distinct improvement in maintenance of key interactions observed after refinement of the initial parameters. Based on the results of the macrolide tests, recommended procedures for parametrizing very large molecules using ffTK are given.
School of Physics and School of Chemistry, Georgia Institute of Technology, Atlanta, 30332, Georgia.
Anna
A
Pavlova
School of Physics and School of Chemistry, Georgia Institute of Technology, Atlanta, 30332, Georgia.
James C
JC
Gumbart
D000465:Algorithms; D000606:Amino Sugars / Q000737:chemistry; D000900:Anti-Bacterial Agents / Q000737:chemistry*; D017963:Azithromycin / Q000737:chemistry*; D001665:Binding Sites; D004917:Erythromycin / Q000737:chemistry*; D004926:Escherichia coli / Q000737:chemistry / Q000378:metabolism; D006601:Hexoses / Q000737:chemistry; D048628:Ketolides / Q000737:chemistry*; D018942:Macrolides / Q000737:chemistry*; D056004:Molecular Dynamics Simulation; D012270:Ribosomes / Q000737:chemistry*; D055672:Static Electricity; D013816:Thermodynamics; D016963:Thermus thermophilus / Q000737:chemistry / Q000378:metabolism; D014867:Water / Q000737:chemistry
D000606:Amino Sugars; D000900:Anti-Bacterial Agents; D006601:Hexoses; D048628:Ketolides; D018942:Macrolides; D014867:Water; C110125:desosamine; C013889:cladinose; D004917:Erythromycin; D017963:Azithromycin; C106791:telithromycin
CHARMM parameters; force field parametrization; force field toolkit; macrolides; ribosome