A method is presented for calculating the conformational free energy of a molecule in all degrees of freedom. The method uses the harmonic approximation with finite integration ranges, along with Mode Scanning, a fast correction for anharmonicity based upon internal bond-angle-torsion coordinates. Mode Scanning accounts for local anharmonicity without the need for expensive Monte Carlo integration. The method is efficient, and comparisons with analytic or highly detailed numerical calculations show excellent accuracy. Similar comparisons for the previously described Mode Integration method show that, although it is computationally demanding, it can be less accurate than the pure harmonic approximation. The inaccuracy of Mode Integration is traceable to its use of a Cartesian coordinate basis set; much more accurate results are obtained when the basis set consists of bond-angle-torsion coordinates.

A fast, accurate method of assigning partial atomic charges is described. The method is based upon the concept of electronegativity equalization and is parametrized to fit electrostatic potentials obtained from ab initio quantum calculations. A novel algorithm for identifying alternate resonance forms is used to ensure that chemically equivalent atoms are assigned equal charges. The resulting charges are independent of conformation, yield good agreement with ab initio electrostatic potentials, and are similar to standard force field charges for common biochemical components. The method is broadly parametrized and generates charges for a drug-like compound in about 0.45 s on a 2.26 GHz Pentium 4 PC. It should thus be useful in a range of applications, such as molecular design and QSAR. The resonance algorithm is expected to have additional applications, such as in atom-typing and detection of molecular symmetry.