Modify force field

Modified force field models based on path integral simulations yield excellent agreement with experiment for thermodynamic properties. 

The performance of the modified force field was evaluated by comparing calculated and experimental relative stability of a series of 1,3-diaza cyclic compounds (19-24). 

Stereo view of the sixty propane minima (thick lines) obtained with the modified force field (see text) on the surface of the A peptide chain (medium lines) of the GCN4 leucine zipper (PDB code 2ZTA). Although the peptide chain was removed during the MCSS procedure, its backbone and hydrophobic side chains are also drawn (thin lines) to show how the propane minima match the aliphatic groups of chain B. Hydrophobic residues are labeled at their Ca atom.Five clusters of propane minima that do not match the hydrophobic side chain of the helix involved in the interhelical interactions are labeled from A (top right) to E (bottom center) and discussed in the text. 

Stereo view of the three lowest energy minima of benzene obtained with the modified force field and the lowest energy minimum of benzamidine (thick lines for heavy atoms and thin lines for polar hydrogens) in the thrombin active site (thin lines). 

This style of refinement also reflected a change of emphasis with respect to the computational balance between initial structure generation and restrained MD. Previously, most workers had spent much time refining structures with respect to distance restraints before applying MD. With this modified force field, it was practical to start MD refinement with crude metric matrix structures after only substructure embedding, or even simply from extended strand initial structures. 

As described earlier, the development time for generating a tailored force field used in CSPs is rather lengthy, and thus such an approach is not possible to use for each compound that a pharmaceutical company is interested in knowing the solid-state properties of [11-13]. Therefore, at AstraZeneca we have over the recent years developed a less time-consuming approach, which is here briefly described [14]. Rather than creating a new force field for a specific molecule, we have relied on the OPLS2005 force field and based on that created an in-house-modified force field— here called Solid State Prediction Tool (SSPT) for the treatment of the intermolecular interactions and for the creation of polymorph landscapes [15,16]. Our calculations typically follow the procedures listed down ... 

If needed, modify force field parameters to match the calculated result with experiment. (Rationalization and validation of the reparameterization is desirable.)... 

Donini O, Weaver DF. Development of modified force field for cation-amino acid interactions ab initio-AerrweA empirical correction terms with comments on cation-rr interactions. JComputChem. 1998 19 1515 25. 

Another exceedingly important validation step for emphatically flexible molecules is to test whether steric parameters derived by averaging the characteristics of a diverse conformational set are capable of reproducing the flexibility of species from the smdied series at the MD level. Due to the unusual behavior of the torsion angles in this class of compounds (the pronounced gauche-effect), it is necessary to generate the probability distribution of the parametrized dihedral angle C-O-C-C and the symmetric C-C-O-C in the MD simulation of diethyl ether in liquid phase in order to check the performance of the modified force field. 

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