Mechanics and Comparison of Force Fields

The Danish University of Pharmaceutical Sciences, Copenhagen, Denmark KLAUS GUNDERTOFTE H. Lundbeck A/S, Copenhagen- Valby, Denmark PER-OLA NORRBY 

Technical University of Denmark, Lyngby, Denmark INGRID PETTERSSON 

Molecular mechanics (force field) calculation is the most commonly used type of calculation in computational medicinal chemistry, and a large number of different force fields have been developed over the years. The results of a molecular mechanics (MM) calculation are highly dependent on the functional forms of the potential energy functions of the force field and of the quality of their parameterization. Thus in order to obtain reliable computational results it is crucial that the merits and limitations of the various available force fields are taken into account. In this chapter, the basic principles of force-field calculations are reviewed, and a comparison of calculated and experimental conformational energies for a wide range of commonly used force fields is presented. As quantum mechanical (QM) methods have undergone a rapid development in the last decade, we have also undertaken a comparison of these force fields with some commonly employed QM methods. The chapter also includes a review of force fields with respect to their abilities to calculate intermolecular interactions. 

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Finally, as solvent effects play an important role in computational medicinal chemistry, a discussion of force-field calculations including solvation is also included in this chapter. 

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Pettersson I, Liljefors T. Molecular mechanics calculated conformational energies of organic molecules a comparison of force fields. In Lipkowitz KB, Boyd DB, eds. Reviews in Computational Chemistry. Vol. 9. New York VCH, 1996 167-189. Liljefors T, Gundertofte K, Norrby PO, Pettersson I. Molecular mechanics and comparsion of force fields. In Bultinck P, Winter HD, Langenaeker W, Tollenaere JP, eds. Computational Medicinal Chemistry for Drug Discovery. New York Marcel Dekker, 2004 1-28. 

Ingrid Pettersson and Tommy Liljefors, Molecular Mechanics Calculated Conformational Energies of Organic Molecules A Comparison of Force Fields. 

Pettersson, 1. and Liljefors, T. 1996. Molecular Mechanics Calculated Conformational Energies of Organic Molecules A Comparison of Force Fields , in Reviews in Computational Chemistry, Vol. 9, Lipkowitz, K. B. and Boyd, D. B., Eds., VCH New York, 167. 

The calculations described here have been called strain calculations, molecular mechanics, or force field calculations. We prefer the latter term. For a discussion of historical developments and a literature survey of earlier work, which are not given here, the reader is referred to a number of other reviews (1-3). The present paper deals with the description of force field types, techniques of energy minimisation, and procedures for the determination of force field parameters, and with some applications, preferentially taken from our own field of interest. In accordance with the experiences of the author, the work of Lifson and coworkers is given special attention other authors are nevertheless well represented in the context of critical comparisons. We hope that this selection, although inevitably biased, will help to improve the consistency of the presentation of the subject. 

Today, there is quite a variety of such potentials [125-132], The performance of potentials for different tasks in structure prediction varies. Reviews and comparisons of database and molecular mechanics force fields as well an discussion of their controversial relationship to free energy can be found in [133-135],... 

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