Molecular mechanics accuracy

A number of issues need to be addressed before this method will become a routine tool applicable to problems as the conformational equilibrium of protein kinase. E.g. the accuracy of the force field, especially the combination of Poisson-Boltzmann forces and molecular mechanics force field, remains to be assessed. The energy surface for the opening of the two kinase domains in Pig. 2 indicates that intramolecular noncovalent energies are overestimated compared to the interaction with solvent. 

The two ways of learning - deductive and inductive - have already been mentioned. Quite a few properties of chemical compounds can be calculated explicitly. Foremost of these are quantum mechanical methods. However, molecular mechanics methods and even simple empirical methods can often achieve quite high accuracy in the calculation of properties. These deductive methods are discussed in Chapter 7. 

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. 

Th e geoinetries obtain ed from opt irn i.ration s with sein i-ern pirical calculations describe the shapes of niolcctiles. I he calculations have varying degrees of accuracy and take more time than molecular mechan ics methods. The accuracy of the results depends on th e m olecti le. 

In order to obtain the best accuracy results as quickly as possible, it is often advantageous to do two geometry optimizations. The first geometry optimization should be done with a faster level of theory, such as molecular mechanics or a semiempirical method. Once a geometry close to the correct geometry has been obtained with this lower level of theory, it is used as the starting geometry for a second optimization at the final, more accurate level of theory. 

It is possible to use computational techniques to gain insight into the vibrational motion of molecules. There are a number of computational methods available that have varying degrees of accuracy. These methods can be powerful tools if the user is aware of their strengths and weaknesses. The user is advised to use ah initio or DFT calculations with an appropriate scale factor if at all possible. Anharmonic corrections should be considered only if very-high-accuracy results are necessary. Semiempirical and molecular mechanics methods should be tried cautiously when the molecular system prevents using the other methods mentioned. 

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. 

One of the major difficulties with molecular mechanics procedures (MMh- or otherwise) is that they almost always fail. That is, you find that force constants are not available for the molecule of interest. This is both the strength and weakness of molecular mechanics it uses atom types to introduce specific chemical environments for the atoms within a molecule (to obtain accuracy in the calculations) but then requires knowledge of force constants specific to that chemical environment (as specific as stating that an atom is in a five-member ring containing one oxygen and one carbon, for example). As the number, N, of atom types rises the number of force constants needed to describe all possible occurrences of these atom type becomes very large. For torsions, for... 

Empirical energy functions can fulfill the demands required by computational studies of biochemical and biophysical systems. The mathematical equations in empirical energy functions include relatively simple terms to describe the physical interactions that dictate the structure and dynamic properties of biological molecules. In addition, empirical force fields use atomistic models, in which atoms are the smallest particles in the system rather than the electrons and nuclei used in quantum mechanics. These two simplifications allow for the computational speed required to perform the required number of energy calculations on biomolecules in their environments to be attained, and, more important, via the use of properly optimized parameters in the mathematical models the required chemical accuracy can be achieved. The use of empirical energy functions was initially applied to small organic molecules, where it was referred to as molecular mechanics [4], and more recently to biological systems [2,3]. 

An alternative approach is to replace an accurate but expensive first-principle-based technique by a reliable model potential. Such potentials, broadly referred to as molecular mechanics (MM), generally cannot account for bond-breaking, but can, in principle, account for the range of intermolecular interactions. However, using a fitted pair-wise potential may result in losing quantitative accuracy, predictability, and the underlying physics. 

Comparison of molecular mechanics force fields and evaluation of calculation accuracy, J. Comp. Chem. 18 449 (1997). 

A. J. Cross, Evaluation of molecular mechanics and calculation accuracy, Chem. Phys. 

Since the parameters used in molecular mechanics contain all of the electronic interaction information to cause a molecule to behave in the way that it does, proper parameters are important for accurate results. MM3(2000), with the included calculation for induced dipole interactions, should model more accurately the polarization of bonds in molecules. Since the polarization of a molecular bond does not abruptly stop at the end of the bond, induced polarization models the pull of electrons throughout the molecule. This changes the calculation of the molecular dipole moment, by including more polarization within the molecule and allowing the effects of polarization to take place in multiple bonds. This should increase the accuracy with which MM3(2000) can reproduce the structures and energies of large molecules where polarization plays a role in structural conformation. 

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