Abstract
Corrinoid cofactors such as cobalamin are used by many enzymes and are essential for most living organisms. Therefore, there is broad interest in investigating cobalamin-protein interactions with molecular dynamics simulations. Previously developed parameters for cobalamins are based mainly on crystal structure data. Here, we report CHARMM-compatible force field parameters for several corrinoids developed from quantum mechanical calculations. We provide parameters for corrinoids in three oxidation states, Co3+, Co2+, and Co1+, and with various axial ligands. Lennard-Jones parameters for the cobalt center in the Co(II) and Co(I) states were optimized using a helium atom probe, and partial atomic charges were obtained with a combination of natural population analysis (NPA) and restrained electrostatic potential (RESP) fitting approaches. The Force Field Toolkit was used to optimize all bonded terms. The resulting parameters, determined solely from calculations of cobalamin alone or in water, were then validated by assessing their agreement with density functional theory geometries and by analyzing molecular dynamics simulation trajectories of several corrinoid proteins for which X-ray crystal structures are available. In each case, we obtained excellent agreement with the reference data. In comparison to previous CHARMM-compatible parameters for cobalamin, we observe a better agreement for the fold angle and lower RMSD in the cobalamin binding site. The approach described here is readily adaptable for developing CHARMM-compatible force-field parameters for other corrinoids or large biomolecules.
Original language | English |
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Pages (from-to) | 784-798 |
Number of pages | 15 |
Journal | Journal of Chemical Theory and Computation |
Volume | 14 |
Issue number | 2 |
DOIs | |
State | Published - Feb 13 2018 |
Funding
This work was supported by awards from NSF (No. MCB- 1452464) and NIH (No. R01-GM123169) to J.C.G. It was also supported by the U.S. Department of Energy (DOE) Office of Science, Biological and Environmental Research, Subsurface Biogeochemical Research (SBR) Program through the Mercury Science Focus Area Program (SFA) at Oak Ridge National Laboratory (ORNL), which is managed by UT-Battelle LLC for the U.S. DOE under Contract No. DE-AC05-00OR22725. This research used resources at the National Energy Research Scientific Computing Center (NERSC), which is supported by the Office of Science of the U.S. DOE under Contract No. DEAC02- 05CH11231, and the Compute and Data Environment for Science (CADES) at ORNL. Additional computational resources were provided via the Extreme Science and Engineering Discovery Environment (XSEDE), which is supported by NSF Grant No. OCI-1053575. We thank Sarah J. Cooper for assistance with figures. This work was supported by awards from NSF (No. MCB-1452464) and NIH (No. R01-GM123169) to J.C.G. It was also supported by the U.S. Department of Energy (DOE) Office of Science, Biological and Environmental Research, Subsurface Biogeochemical Research (SBR) Program through the Mercury Science Focus Area Program (SFA) at Oak Ridge National Laboratory (ORNL), which is managed by UT-Battelle LLC for the U.S. DOE under Contract No. DE-AC05-00OR22725. This research used resources at the National Energy Research Scientific Computing Center (NERSC), which is supported by the Office of Science of the U.S. DOE under Contract No. DE-AC02-05CH11231, and the Compute and Data Environment for Science (CADES) at ORNL. Additional computational resources were provided via the Extreme Science and Engineering Discovery Environment (XSEDE), which is supported by NSF Grant No. OCI-1053575. We thank Sarah J. Cooper for assistance with figures.