Indeed, it was originally conceived as “a combined organic/protein force field that is equally applicable to proteins and other systems of biological significance”. The Merck Molecular Force Field (MMFF94), on the other hand, was developed with the explicit goal of performing MD simulations on pharmaceutically relevant systems in the condensed phase. 17 Nevertheless, this force field has not been evaluated in a condensed phase, high-dielectric medium, and may be assumed to be unsuitable for condensed phase studies of, for example, drug-protein interactions. As a special case, Allinger’s most recent MM4 force field accurately predicts gas-phase conformational energetics of organic molecules and includes terms that account for polarizability in an approximate way. Indeed, as classical additive force fields do not account for polarizability, a given additive force field will only perform well in a given dielectric medium.
Here, we will limit our discussion to force fields that were parametrized to reproduce condensed phase properties. To date, a number of force fields with wide coverage of drug-like molecules are available. However, its coverage of the wide range of chemical space required for the field of computational medicinal chemistry is limited. Apart from proteins, 7 it supports nucleic acids 8 – 10 and lipids, 11, 12 and has limited support for carbohydrates, 13 – 15 with a more complete carbohydrate extension in preparation, 16 allowing simulations on all commonly encountered motifs in biological systems. Towards this goal the CHARMM additive, all-atom force field 6 has made an important contribution. 3 While greater computational resources, including massively parallel architectures, and efficient codes such as NAMD 4 and Desmond 5 have made important contributions to these advances, the quality of the force fields that act as the framework of computational biochemistry and biophysics have improved to the point that stable simulations of these systems are possible. Recent examples include simulations of the nucleosome, 1 ion channels 2 and the ribosome. CGenFF thus makes it possible to perform “all-CHARMM” simulations on drug-target interactions thereby extending the utility of CHARMM force fields to medicinally relevant systems.Ĭomputational biochemistry and biophysics is an ever growing field that is being applied to a wide range of heterogeneous systems of increasing size and complexity. Additionally, the parametrization procedure, described fully in the present paper in the context of the model systems, pyrrolidine, and 3-phenoxymethylpyrrolidine will allow users to readily extend the force field to chemical groups that are not explicitly covered in the force field as well as add functional groups to and link together molecules already available in the force field. Statistics related to the quality of the parametrization with a focus on experimental validation are presented. The parametrization philosophy behind the force field focuses on quality at the expense of transferability, with the implementation concentrating on an extensible force field. The resulting CHARMM General Force Field (CGenFF) covers a wide range of chemical groups present in biomolecules and drug-like molecules, including a large number of heterocyclic scaffolds. In the present paper an extension of the CHARMM force field to drug-like molecules is presented. The widely used CHARMM additive all-atom force field includes parameters for proteins, nucleic acids, lipids and carbohydrates.
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