Molecular dynamics simulations have revolutionized chemistry by allowing cheap and fast in silico analyses of numerous systems of interest. Despite various advancements, many applications still require costly experimental input in order to guide direction, as the results from simulations are not yet accurate enough to rely on alone. This is particularly problematic in drug design, where accurate binding affinity measurements could greatly improve the ability to discover drugs. In this thesis, I discuss a philosophy behind improving force-fields, the functions which provide the configurational energies in simulations, for binding calculations. I show a new approach to non-bonded force-field parameterization, which reduces the number of parameters used and also preserves the chemical uniqueness of each atom in a molecule. Secondly, I discuss a synthesis pathway towards generating novel host molecules for parameterization of force-fields built for binding calculations. Lastly, I present a novel and systematic analysis of experimental uncertainties in isothermal titration calorimetry data, to establish a clearer foundation for their use in force field parameterization. Taken together, these efforts contribute to an overall goal of developing force-fields that yield more accurate binding calculations.