  Neutron scattering and molecular dynamics studies were performed on a
concentrated aqueous tetramethylammonium (TMA) chloride solution to gain
insight into the hydration shell structure of TMA, which is relevant for
understanding its behavior in biological contexts of, e.g., properties of
phospholipid membrane headgroups or interactions between DNA and histones.
Specifically, neutron diffraction with isotopic substitution experiments were
performed on TMA and water hydrogens to extract the specific correlation
between hydrogens in TMA ($\mathrm{H_{TMA}}$) and hydrogens in water
($\mathrm{H_{W}}$). Classical molecular dynamics simulations were performed to
help interpret the experimental neutron scattering data. Comparison of the
hydration structure and simulated neutron signals obtained with various force
field flavors (e.g. overall charge, charge distribution, polarity of the CH
bonds and geometry) allowed us to gain insight into how sensitive the TMA
hydration structure is to such changes and how much the neutron signal can
capture them. We show that certain aspects of the hydration, such as the
correlation of the hydrogen on TMA to hydrogen on water, showed little
dependence on the force field. In contrast, other correlations, such as the
ion-ion interactions, showed more marked changes. Strikingly, the neutron
scattering signal cannot discriminate between different hydration patterns.
Finally, ab initio molecular dynamics was used to examine the three-dimensional
hydration structure and thus to benchmark force field simulations. Overall,
while neutron scattering has been previously successfully used to improve force
fields, in the particular case of TMA we show that it has only limited value to
fully determine the hydration structure, with other techniques such as ab
initio MD being of a significant help.
