Assessing the Conformational Equilibrium of Carboxylic Acid via Quantum Mechanical and Molecular Dynamics Studies on Acetic Acid

Accurate
hydrogen placement in molecular modeling is crucial for
studying the interactions and dynamics of biomolecular systems. The
carboxyl functional group is a prototypical example of a functional
group that requires protonation during structure preparation. To our
knowledge, when in their neutral form, carboxylic acids are typically
protonated in the syn conformation by default in
classical molecular modeling packages, with no consideration of alternative
conformations, though we are not aware of any careful examination
of this topic. Here, we investigate the general belief that carboxylic
acids should always be protonated in the syn conformation.
We calculate and compare the relative energetic stabilities of syn and anti acetic acid using ab initio quantum mechanical calculations and atomistic
molecular dynamics simulations. We focus on the carboxyl torsional
potential and configurations of microhydrated acetic acid from molecular
dynamics simulations, probing the effects of solvent, force field
(GAFF vs GAFF2), and partial charge assignment of acetic acid. We
show that while the syn conformation is the preferred
state, the anti state may in some cases also be present
under normal NPT conditions in solution.