Effect of the Conformational Kinetic Energy and the Rotovibrational Coupling in the Conformational Population of Bioactive Compounds

This work presents the determination of a semiclassical conformational partition function for bioactive compounds. The proposed partition function includes the effect of the rotovibrational coupling and the conformational kinetic energy, through the rotovibrational G matrix. In addition, the model considers a relaxed potential that includes the effect of the nonconformational, internal, coordinates. Comparison of results from harmonic and anharmonic vibrational models shows that the present partition function is a good approximation to the quantum one. The effect of the rotovibrational coupling and conformational kinetic energy, i.e. the G matrix, on the partition function is analyzed considering the biologically active, protonated, forms of nicotine and the nicotinic analgesic ABT-594. All energetic and structural data are derived from ab initio results at the MP2/cc-pVDZ level. Only two conformers are found to be significantly populated at physiological temperature in the nicotine case. The relative population of both conformers is clearly affected by the value of the G matrix. For ABT-594, several minima on the conformational potential energy hypersurface are found. However, only one conformer collects the population. Here, the distribution of population is only slightly affected by the G matrix. Performing simulations with a double minima potential, we show that for conformers separated by energy differences about or higher than 2 kcal mol-1, the effect of the G matrix can be neglected.