Development of a grid search molecular mechanics modeling strategy to study elution behavior in cyclodextrin modified capillary electrophoresis

Novel methods to use molecular mechanics (MM) in modeling solute-receptor i nteractions are developed that are pertinent to computational studies of dy namic separation or sensing processes. Specifically, a grid search MM model ing approach is used to study separation behavior in cyclodextrin (CD)-modi fied capillary electrophoresis (CE). Laboratory CE separations of di-substi tuted naphthalene compounds are accomplished employing an anionic, single i somer carboxymethyl-CD as a running buffer additive. Computational work inv olved the docking of these solutes into the cavity of this CD using a syste matic grid search to probe the interaction space. It was discovered that th e size of incremental changes in position and dimensional freedom in defini ng the grid are significant parameters. At each grid position the configura tion of the atoms in the complex is altered in a process to minimize energy . It was discovered that comprehensive minimization involving many iterations of the process is extremely important ill locating true low energy conform ers. Interaction energy contours, involving translation and rotation of the solute into the CD cavity, are produced that graphically reveals the stren gth of the CD-solute interaction. Increasing the number of minimization ite rations from 100s to 1000s resulted in remarkable changes in those contours , and improved the correlation between computationally determined and exper imental distribution coefficients. The correct ordering of distribution coe fficients was achieved with a few approaches, but with the comprehensive mi nimization approach experimental and computational coefficients were genera lly within a factor of 4 of each other. Moreover, the comprehensive minimiz ation approach resulted in many points in the grid search, micro-positional states, that minimized to a single conformer. Consideration of the degener acy of these states is also shown to be significant.