Force field methods limitations

Computational chemists in the pharmaceutical industry also expanded from their academic upbringing by acquiring an interest in force field methods, QSAR, and statistics. Computational chemists with responsibility to work on pharmaceuticals came to appreciate the fact that it was too limiting to confine one s work to just one approach to a problem. To solve research problems in industry, one had to use the best available technique, and this did not mean going to a larger basis set or a higher level of quantum mechanical theory. It meant using molecular mechanics or QSAR or whatever. 

The molecular mechanics (MM) or force field method is an empirical method based on classical mechanics and adjustable parameters. It has the disadvantage of being limited in its application to certain kinds of compounds for which the required parameters have been determined (experimentally or by theoretical calculations). Its advantage is a considerably shorter computation time in comparison with other procedures having the same purpose. This method has been shown to be very reliable and efficient in determing molecular geometries, energies, and other properties for a wide variety of compounds. 

Summarizing, the purpose of this review is not to give a more or less complete coverage of the literature, but rather to illuminate the present scope and limitations of the force-field method and to draw guidelines for the future. We prefer to concentrate our attention mainly on theoretical results, on open questions, and on selected applications taken from recent work of leading experts in the area. A larger body of older but still relevant literature on the FF method and related topics has been covered in an extensive review by Williams et al. 

The EFP method attempts to overcome this parameterization problem by including electrostatics and polarization from first principles. This represents a considerable departure from the traditional MM potentials used in biomolecular simulations. The electrostatic energy remains an approximation, however, as the multipole expansions in Ueie are left uncorrected for the effects of charge penetration (C/pen). This penetration energy, Upen, is then implicit in Urep. Thus a limitation that is characteristic of all force-field methods, from the crudest MM to the most sophisticated QM/MM, is a certain lack of generality, i.e., there are arbitrary parameters that have to be refined and fitted for a particular application. 

The force-field method involves the other part of the Born-Oppenheimer approximation, that is the positioning of the nuclei. The electronic system is not considered explicitly, but its effects are of course taken into account indirectly. This method is often referred to as a classical approach, not because the equations and parameters are derived from classical mechanics, but rather because it is assumed that a set of equations exist which are of the form of the classical equations of motion. The problem from this point of view is one of establishing just which equations are necessary, and determining the numerical values for the constants which appear in the equations. In general there is no limit as to what functions may be chosen or what parameters arc to be used, except that the force-field must duplicate the experimental data. 

The force-field method which will be discussed here presents a useful method for determining the structure and energy of a molecule. Both structure and energy seem to be of primary importance. There are many other properties of a molecule that can be determined, after the structure and/or energy are known, or they can be determined simultaneously with the structure and energy. These include the Raman and infrared spectra, and the other thermodynamic functions. Since these quantities are of limited use to organic chemists, we will concentrate here on just structure and energy (gas phase) at 25°C. 

We continue to believe that the force-field method offers a rapid, convenient and reliable method for the determination of molecular structures and energies. While there are limitations to the method, as there are with each of the experimental methods, the usefulness of this technique now seems generally appreciated. We can forsee only a continuing expansion of the development and applications of force-field calculations in many areas of chemistry. 

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