Assessment of an Electrostatic Energy-Based Charge Model for Modeling the Electrostatic Interactions in Water Solvent

The
protein force field based on the restrained electrostatic
potential
(RESP) charges has limitations in accurately describing hydrogen bonding
interactions in proteins. To address this issue, we propose an alternative
approach called the electrostatic energy-based charges (EEC) model,
which shows improved performance in describing electrostatic interactions
(EIs) of hydrogen bonds in proteins. In this study, we further investigate
the performance of the EEC model in modeling EIs in water solvent.
Our findings demonstrate that the fixed EEC model can effectively
reproduce the quantum mechanics/molecular mechanics (QM/MM)-calculated
EIs between a water molecule and various water solvent environments.
However, to achieve the same level of computational accuracy, the
electrostatic potential (ESP) charge model needs to fluctuate according
to the electrostatic environment. Our analysis indicates that the
requirement for charge adjustments depends on the specific mathematical
and physical representation of EIs as a function of the environment
for deriving charges. By comparing with widely used empirical water
models calibrated to reproduce experimental properties, we confirm
that the performance of the EEC model in reproducing QM/MM EIs is
similar to that of general purpose TIP4P-like water models such as
TIP4P-Ew and TIP4P/2005. When comparing the computed 10,000 distinct
EI values within the range of −40 to 0 kcal/mol with the QM/MM
results calculated at the MP2/aug-cc-pVQZ/TIP3P level, we noticed
that the mean unsigned error (MUE) for the EEC model is merely 0.487
kcal/mol, which is remarkably similar to the MUE values of the TIP4P-Ew
(0.63 kcal/mol) and TIP4P/2005 (0.579 kcal/mol) models. However, both
the RESP method and the TIP3P model exhibit a tendency to overestimate
the EIs, as evidenced by their higher MUE values of 1.761 and 1.293
kcal/mol, respectively. EEC-based molecular dynamics simulations have
demonstrated that, when combined with appropriate van der Waals parameters,
the EEC model can closely reproduce oxygen–oxygen radial distribution
function and density of water, showing a remarkable similarity to
the well-established TIP4P-like empirical water models. Our results
demonstrate that the EEC model has the potential to build force fields
with comparable accuracy to more sophisticated empirical TIP4P-like
water models.