Force Fields and Docking

Of particular interest in the field of drug design is the prediction of the strength and specificity with which a small to medium sized molecule may bind to a biological macromolecule (Lazaridis 2002 Shoichet et al. 2002). Many drugs function by binding to the active sites of particular enzymes so strongly that the normal substrates of these enzymes are unable to displace them and as a result some particular biochemical pathway is stalled. 

One way to make this process somewhat more efficient is to adopt rigid structures for the various molecules. Thus, one does not attempt to perform geometry optimizations, but simply puts the molecules in some sort of contact and evaluates their interaction energies. To that extent, one needs only to evaluate non-bonded terms in the force field, like those 

Synopsis of Stahl etal. (1991), Conformational Analysis with Carbon-Carbon Coupling Constants. A Density Functional and Molecular Mechanics Study . 

Deconvolution of such spectra can be accomplished in a computational fashion by 

4-dimethylhex-5-ene, where the conformer energies were determined using the MM3 force field and the NMR coupling constants were predicted at the density functional level of theory. As density functional tlieory is the subject of Chapter 8 and the prediction of NMR data is not discussed until Section 9.4, we will focus here simply on the performance of MM3 for predicting conformer energies and weighting spectral data. 

---

Some force fields and docking procedures work with the concept of essential hydrogens, i.e., hydrogens bonded to heteroatoms or hydrogens that could be involved in formation of a hydrogen bond. It is important to adhere to the procedure used to calibrate the docking program and to apply the correct method of protonation. 

For an MD approach with QM/MM design a protocol (preequilibration with a classical force field, substrate docking, boundary conditions, number and length of sampling windows, etc.). 

The treatment of receptor flexibility is likely to be an area of increased research activity in the near future. It is already being considered in the related area of ligand docking into receptors. 4,i45 -pije incorporation of limited side chain mobility should be straightforward in de novo design methods that are controlled by force fields and also in interaction-site-based methodologies, where methods similar to those adopted by Jones et al. s could be used. 

The affinity of interactions can be calculated in a number of ways. One example is the force field method to calculate the free energy of binding for the Ugand-protein system before and after the docking, as given by the equation... 

---