COFFDROP: A Coarse-Grained Nonbonded Force Field for Proteins Derived from All-Atom Explicit-Solvent Molecular Dynamics Simulations of Amino Acids

We describe the derivation of a set
of bonded and nonbonded coarse-grained
(CG) potential functions for use in implicit-solvent Brownian dynamics
(BD) simulations of proteins derived from all-atom explicit-solvent
molecular dynamics (MD) simulations of amino acids. Bonded potential
functions were derived from 1 μs MD simulations of each of the
20 canonical amino acids, with histidine modeled in both its protonated
and neutral forms; nonbonded potential functions were derived from
1 μs MD simulations of every possible pairing of the amino acids
(231 different systems). The angle and dihedral probability distributions
and radial distribution functions sampled during MD were used to optimize
a set of CG potential functions through use of the iterative Boltzmann
inversion (IBI) method. The optimized set of potential functionswhich
we term COFFDROP (COarse-grained Force Field for Dynamic Representation
Of Proteins)quantitatively reproduced all of the “target”
MD distributions. In a first test of the force field, it was used
to predict the clustering behavior of concentrated amino acid solutions;
the predictions were directly compared with the results of corresponding
all-atom explicit-solvent MD simulations and found to be in excellent
agreement. In a second test, BD simulations of the small protein villin
headpiece were carried out at concentrations that have recently been
studied in all-atom explicit-solvent MD simulations by Petrov and
Zagrovic (PLoS Comput. Biol. 2014, 5, e1003638). The anomalously strong intermolecular interactions
seen in the MD study were reproduced in the COFFDROP simulations;
a simple scaling of COFFDROP’s nonbonded parameters, however,
produced results in better accordance with experiment. Overall, our
results suggest that potential functions derived from simulations
of pairwise amino acid interactions might be of quite broad applicability,
with COFFDROP likely to be especially useful for modeling unfolded
or intrinsically disordered proteins.