Accurate Description of Solvent-Exposed Salt Bridges with a Non-polarizable Force Field Incorporating Solvent Effects

The strength of salt bridges resulting from the interaction
of
cations and anions is modulated by their environment. However, polarization
of the solvent molecules by the charged moieties makes the accurate
description of cation–anion interactions in an aqueous solution
by means of a pairwise additive potential energy function and classical
combination rules particularly challenging. In this contribution,
aiming at improving the representation of solvent-exposed salt-bridge
interactions with an all-atom non-polarizable force field, we put
forth here a parametrization strategy. First, the interaction of a
cation and an anion is characterized by hybrid quantum mechanical/molecular
mechanics (QM/MM) potential of mean force (PMF) calculations, whereby
constantly exchanging solvent molecules around the ions are treated
at the quantum mechanical level. The Lennard–Jones (LJ) parameters
describing the salt-bridge ion pairs are then optimized to match the
reference QM/MM PMFs through the so-called nonbonded FIX, or NBFIX,
feature of the CHARMM force field. We apply the new set of parameters,
coined CHARMM36m-SBFIX, to the calculation of association constants
for the ammonium–acetate and guanidinium–acetate complexes,
the osmotic pressures for glycine zwitterions, guanidinium, and acetate
ions, and to the simulation of both folded and intrinsically disordered
proteins. Our findings indicate that CHARMM36m-SBFIX improves the
description of solvent-exposed salt-bridge interactions, both structurally
and thermodynamically. However, application of this force field to
the standard binding free-energy calculation of a protein–ligand
complex featuring solvent-excluded salt-bridge interactions leads
to a poor reproduction of the experimental value, suggesting that
the parameters optimized in an aqueous solution cannot be readily
transferred to describe solvent-excluded salt-bridge interactions.
Put together, owing to their sensitivity to the environment, modeling
salt-bridge interactions by means of a single, universal set of LJ
parameters remains a daunting theoretical challenge.