Development of CHARMM-Compatible Force-Field Parameters for Cobalamin and Related Cofactors from Quantum Mechanical Calculations

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.