Fixed-charge molecular mechanics force fields have been a workhorse of biomolecular simulation since the first simulations of proteins were performed more than four decades ago. Such force fields generally consist of relatively simple harmonic and periodic potentials to represent bonded interactions and the Coulomb and Lennard-Jones potentials to represent nonbonded electrostatic and van der Waals interactions, respectively. The key to the success of these models is their relatively low computational expense while providing nonbonded interactions that are reasonably accurate despite the neglect of electronic polarization, charge transfer, and a host of other important electrostatic phenomena. This is usually accomplished in a "mean field" way by utilizing partial atomic charges that correspond to molecular electron distributions that are overpolarized relative to the gas phase (i.e., more polar than would be expected for the gas phase), which is a sensible approach given that such simulations are generally performed in the condensed phase. There are many ways to achieve this overpolarization. Some force fields derive these partial atomic charges in an empirical way using condensed phase experimental data. Other force fields derive these charges in an ab initio way using some type of electronic structure calculation. One specific set of force fields utilizing the latter approach are the AMBER family of biomolecular force fields based on AMBER ff94 and the GAFF small molecule force field . This family of force fields relies on charges fit -in a two-step procedure with restraints -to reproduce molecular electrostatic potentials (ESPs) generated using the HF/6-31G* 8-10 method and basis set combination. Alternatively charges for GAFF may be generated using the AM1-BCC method that is parameterized to reproduce HF/6-31G* ESPs, but has some corrections that were hand-tuned to reproduce hydration free energies. It is commonly believed that HF/6-31G* combination results in charge distributions that are fortuitously 10-15% more polar than gas phase. This is generally regarded as a desirable feature for condensed phase simulation, as any liquid (or solid) environment will have a dielectric constant greater than 1 and therefore overpolarize the molecule(s) in question relative to gas phase.