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. Speciőcally, neutron
diffraction with isotopic substitution experiments were performed on TMA and water hydrogens to
extract the speciőc correlation between hydrogens in TMA (HTMA) and hydrogens in water (HW).
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 őeld ŕavors (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 őeld. In contrast, other correlations, such as the ionśion 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 őeld simulations. Overall, while neutron scattering has been
previously successfully used to improve force őelds, 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 signiőcant help.