Molecular mechanics parameterization

Organic molecules are generally composed of covalent bonded atoms with several well-defined hybridization states tending to have well-understood preferred geometries. This makes them an ideal case for molecular mechanics parameterization. Likewise, organic molecules are the ideal case for semiempirical parameterization. 

Norman L. Allinger and Phillip Bowen (The University of Georgia) Molecular Mechanics Parameterization of Organic Phosphites. ... 

In general, there is an art and a science to molecular mechanics parameterization. On one extreme, least-squares methods can be used to optimize the parameters to best fit the available data set, and reviews on this topic are avail-able. Alternatively, parameters can be determined on a trial-and-error basis. The situation in either case is far from straightforward because the data usually available come from a variety of sources, are measured by different kinds of experiments in different units, and have relative importances that need subjective assessment. Therefore, straightforward applications of least-squares methods are not expected to give optimum results. 

For this reason, there has been much work on empirical potentials suitable for use on a wide range of systems. These take a sensible functional form with parameters fitted to reproduce available data. Many different potentials, known as molecular mechanics (MM) potentials, have been developed for ground-state organic and biochemical systems [58-60], They have the advantages of simplicity, and are transferable between systems, but do suffer firom inaccuracies and rigidity—no reactions are possible. Schemes have been developed to correct for these deficiencies. The empirical valence bond (EVB) method of Warshel [61,62], and the molecular mechanics-valence bond (MMVB) of Bemardi et al. [63,64] try to extend MM to include excited-state effects and reactions. The MMVB Hamiltonian is parameterized against CASSCF calculations, and is thus particularly suited to photochemistry. 

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. 

The accuracy of a molecular mechanics or seim-eni pineal quantum mechanics method depends on the database used to parameterize the method. This is true for the type of molecules and the physical and chemical data in the database. Frequently, these methods give the best results for a limited class of molecules or phen omen a. A disad van tage of these methods is that you m u si have parameters available before running a calculation. Developing param eiers is time-consuming. 

All the constants in these equations must be obtained from experimental data or an ah initio calculation. The database of compounds used to parameterize the method is crucial to its success. A molecular mechanics method may be parameterized against a specific class of molecules, such as proteins or nucleotides. Such a force field would only be expected to have any relevance in... 

Most researchers do not parameterize force fields because many good force fields have already been developed. On rare occasions, a researcher will add an additional atom as described in Chapter 29. The following are some commonly used molecular mechanics force fields. Many of these have been implemented in more than one software package. There tend to be minor differences in the implementation leading to small differences in results from one software package to another. 

Assisted model building with energy refinement (AMBER) is the name of both a force field and a molecular mechanics program. It was parameterized specifically for proteins and nucleic acids. AMBER uses only five bonding and nonbonding terms along with a sophisticated electrostatic treatment. No cross terms are included. Results are very good for proteins and nucleic acids, but can be somewhat erratic for other systems. 

For molecular mechanics, the charge calculation method used in parameterizing the force field should be used if possible. Otherwise, use Q-equilibrate or electrostatic charges. 

It is occasionally desirable to add new parameters to a molecular mechanics force field. This might mean adding an element that is not in the parameterization set or correctly describing a particular atom in a specihc class of molecules. 

Molecular mechanics and semiempirical calculations are all relativistic to the extent that they are parameterized from experimental data, which of course include relativistic effects. There have been some relativistic versions of PM3, CNDO, INDO, and extended Huckel theory. These relativistic semiempirical calculations are usually parameterized from relativistic ah initio results. 

A number of molecular mechanics force fields have been parameterized for specific organic systems, such as proteins or hydrocarbons. There are also a... 

Nearly every technical difficulty known is routinely encountered in transition metal calculations. Calculations on open-shell compounds encounter problems due to spin contamination and experience more problems with SCF convergence. For the heavier transition metals, relativistic effects are significant. Many transition metals compounds require correlation even to obtain results that are qualitatively correct. Compounds with low-lying excited states are difficult to converge and require additional work to ensure that the desired states are being computed. Metals also present additional problems in parameterizing semi-empirical and molecular mechanics methods. 

In the past, when molecular mechanics methods were used for transition metals, it was by having a set of parameters for the metal that were parameterized specifically for one class of compounds. There have been a number of full periodic table force fields created, with the most successful being the UFF force field. All the full periodic molecular mechanics methods still give completely unreasonable results for certain classes of compounds. 

Molecular mechanics force fields are sometimes parameterized to describe lanthanides and actinides. This has been effective in describing the shape of the molecule, but does not go very far toward giving systematic energies. A few semiempirical methods have been parameterized for these elements, but they have not seen widespread use. 

Ah initio calculations of polymer properties are either simulations of oligomers or band-structure calculations. Properties often computed with ah initio methods are conformational energies, polarizability, hyperpolarizability, optical properties, dielectric properties, and charge distributions. Ah initio calculations are also used as a spot check to verify the accuracy of molecular mechanics methods for the polymer of interest. Such calculations are used to parameterize molecular mechanics force fields when existing methods are insulficient, which does not happen too often. 

Molecular mechanics methods have been used particularly for simulating surface-liquid interactions. Molecular mechanics calculations are called effective potential function calculations in the solid-state literature. Monte Carlo methods are useful for determining what orientation the solvent will take near a surface. Molecular dynamics can be used to model surface reactions and adsorption if the force held is parameterized correctly. 

HyperChem uses two types of methods in calculations molecular mechanics and quantum mechanics. The quantum mechanics methods implemented in HyperChem include semi-empirical quantum mechanics method and ab initio quantum mechanics method. The molecular mechanics and semi-empirical quantum mechanics methods have several advantages over ab initio methods. Most importantly, these methods are fast. While this may not be important for small molecules, it is certainly important for biomolecules. Another advantage is that for specific and well-parameterized molecular systems, these methods can calculate values that are closer to experiment than lower level ab initio techniques. 

Molecular mechanics force fields have much information built into them and can be accurate for the molecules used in their parameterization. For molecules outside the limited scope for 40. Dewar, J. S. Dieter, K M. J. Am. Chem. Soc. 108 8075, 1986. 

Vibrational spectroscopy has played a very important role in the development of potential functions for molecular mechanics studies of proteins. Force constants which appear in the energy expressions are heavily parameterized from infrared and Raman studies of small model compounds. One approach to the interpretation of vibrational spectra for biopolymers has been a harmonic analysis whereby spectra are fit by geometry and/or force constant changes. There are a number of reasons for developing other approaches. The consistent force field (CFF) type potentials used in computer simulations are meant to model the motions of the atoms over a large ranee of conformations and, implicitly temperatures, without reparameterization. It is also desirable to develop a formalism for interpreting vibrational spectra which takes into account the variation in the conformations of the chromophore and surroundings which occur due to thermal motions. 

Molecular mechanics is a useful and reliable computational method for structure, energy, and other molecular properties. The mathematical basis for molecular models in MM3 has been described, along with the limitations of the method. One of the major difficulties associated with molecular mechanics, in general, and MM3 in particular is the lack of accurately parameterized diverse functional groups. This lack of diverse functional groups has severely limited the use of MM3 in pharmaceutical applications. 

Theoretical models include those based on classical (Newtonian) mechanical methods—force field methods known as molecular mechanical methods. These include MM2, MM3, Amber, Sybyl, UFF, and others described in the following paragraphs. These methods are based on Hook s law describing the parabolic potential for the stretching of a chemical bond, van der Waal s interactions, electrostatics, and other forces described more fully below. The combination assembled into the force field is parameterized based on fitting to experimental data. One can treat 1500-2500 atom systems by molecular mechanical methods. Only this method is treated in detail in this text. Other theoretical models are based on quantum mechanical methods. These include ... 

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