Parameterization of Force Fields

Using the CFF method, a torsional angle of 75° has been found, which upon improvement of the torsional potential by Ermer decreased to 43.3° (11). The latter value is very similar to the MM 1 and MM2 results, which gave 45.2-44° (76,77). Nevertheless, the parameterization of force fields for highly distorted olefins such as 64-66 would become more reliable if the elusive olefin 64 could be prepared and its structure elucidated. 

Parameterization of force fields for lipids is at an early stage of development in comparison to what has been done for proteins and nucleic acids. Most simulations on lipid systems using force fields have employed parameter sets and parameterization procedures that have proven satisfactory for related systems (i.e., alkane simulations, etc.). This appears to be a reasonable approach, but there are clear cases warranting improvement in the model (e.g., obtaining accurate order parameter profiles). 

In view of the time and possible errors involved in fitting force-field parameters to a large amount of experimental data, the degree of parameterization must be kept to a minimum. Contrary to this is the desire to optimize as large a range of compounds as possible with the same and constant set of force-field parameters, which requires a moderately high degree of parameterization. Automatic procedures for the parameterization of force fields have been developed [100-102]. 

The energy associated with internal molecular rearrangements, such as torsional rotation in alkyl chains can also be obtained and used to gain chemical insight as well as in the parameterization of force fields. 

Faller, R., Schmitz, H., Biermann, O., Miiller-Plathe, F. Automatic parameterization of force fields for liquids by simplex optimization. J. Comp. Chem. 20, 1009-1017 (1999)... 

Wang, J.M., Kollman, P.A. Automatic parameterization of force field by systematic search and genetic algorithms. J. Comp. Chem. 22, 1219-1228 (2001)... 

Let us emphasize that the design and parameterization of force fields for complicated molecular systems is a difficult task as the properties of the system may only be realized via extensive simulation. In particular, where molecular models are used to make predictions in thermodynamic regimes that are far from available experimental data, the results can occasionally be unpredictable. For example, a NAMD [302] case study simulating the melting of ice demonstrates the care needed... 

H-bonded base pairs are stabilized mainly by electrostatic attraction. The high-level ab initio calculations provide reliable data on the energetics of H-bonding which can be used for verification and parameterization of force fields and as a substitution for the missing experimental data. 

The classical introduction to molecular mechanics calculations. The authors describe common components of force fields, parameterization methods, and molecular mechanics computational methods. Discusses th e application of molecular mechanics to molecules comm on in organic,and biochemistry. Several chapters deal w ith thermodynamic and chemical reaction calculations. 

AMBER, BIO-h and OPLS scale 1 van der Waals and 1 electrostatic interactions. Although the value of the 1 nonbonded scale factors is an option in HyperChem, you should generally use recommended values. This is because during parameterization, the force field developers used particular values for the 1 nonbonded scale factors, and their parameters may not be correct for other scale factors. 

The parameterization process may be done sequentially or in a combined fashion. In the sequential method a certain class of compound, such as hydrocarbons, is parameterized first. These parameters are held fixed, and a new class of compound, for example alcohols and ethers, is then parameterized. Tins method is in line with the basic assumption of force fields parameters are transferable. The advantage is that only a fairly small number of parameters are fitted at a time. The ErrF is therefore a relatively low-dimensional function, and one can be reasonably certain that a good minimum has been found (although it may not be the global minimum). The disadvantage is that the final set of parameters necessarily provides a poorer fit (as defined from the value of the ErrF) than if all the parameters are fitted simultaneously. 

Those who attempt to parameterize empirical force field potential functions are embarrassed by serious inconsistencies in the structure of bicyclol2.2.1]heptane, an important molecule as determined by various physical measurements. A structure (11) was synthesized ... 

The molecular mechanics method is extremely parameter dependent. A force field equation that has been empirically parameterized for calculating peptides must be used for peptides it cannot be applied to nucleic acids without being re-parameterized for that particular class of molecules. Thankfully, most small organic molecules, with molecular weights less than 800, share similar properties. Therefore, a force field that has been parameterized for one class of drug molecules can usually be transferred to another class of drug molecules. In medicinal chemistry and quantum pharmacology, a number of force fields currently enjoy widespread use. The MM2/MM3/MMX force fields are currently widely used for small molecules, while AMBER and CHARMM are used for macromolecules such as peptides and nucleic acids. 

The answer to the first question is obvious, if not necessarily trivial one should pick the force field that has previously been shown to be most effective for the most closely related problem one can find. That demonstration of effectiveness may have taken place within the process of parameterization (i.e., if one is interested in conformational properties of proteins, one is more likely to be successful with a force field specifically parameterized to model proteins than with one which has not been) or by post-development validation. Periodically in the literature, papers appear comparing a wide variety of force fields for some well-defined problem, and the results can be quite useful in guiding the choices of subsequent... 

Comba, P. and Remenyi, R. 2003. Inorganic and Bioinorganic Molecular Mechanics Modeling-the Problem of Force Field Parameterization , Coord. Chem. Rev., 238-239, 9. 

Also, metal ion directed stereoselective syntheses often involve organometallic complexes. While there is no fundamental difference between metal-carbon and metal-heteroatom bonds, modeling rc-bonded ligands is not trivial.1 Given a known reaction mechanism (which is not possible for many catalytic reactions), the main problem is the parameterization of the potential energy functions for the intermediates and transition states. The problem is that force field parameters are generally carefully fitted to experimental results, i.e., structures or other data related to the output of force field calculations of the type of compound to be modeled have to be available. For short-lived transition states this is a considerable problem. 

As discussed in Part I (e. g. Chapter 2, Section 2.1), this assumption depends on the type of force field used, i. e., whether there is any link between the parameterization and thermodynamic or spectroscopic (i.e., physically meaningful) parameters. 

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