COMPUTER-SIMULATIONS OF CYCLIC AND ACYCLIC CHOLINERGIC AGONISTS - CONFORMATIONAL SEARCH AND MOLECULAR-DYNAMICS SIMULATIONS

Molecular dynamics simulations have been performed on aqueous solution s of two chemically similar nicotinic cholinergic agonists in order to compare their structural and dynamical differences. The cyclic 1,1-di methyl-4-acetylpiperazinium iodide (H PIP) molecule was previously sho wn to be a strong agonist for nicotinic acetylcholine receptors (McGro ddy et al., 1993), while the acyclic N, N, N, N'-tetramethyl-N'-acetyl ethylenediamine iodide (HTED) derivative is much less potent. These di fferences were expected to arise from differences in the solution stru ctures and internal dynamics of the two molecules. HPIP was originally thought to be relatively rigid; however, molecular dynamics simulatio ns suggest that the acetyl portion of the molecule undergoes significa nt ring dynamics on a psec timescale. The less constrained HTED molecu le is relatively rigid, with only one transition observed about any of the major dihedrals in four 100 psec simulations, each started from a different conformation. The average structures obtained from the simu lations are very similar to the starting minimized structure in each c ase, except for the HTED simulation where a single rotation about the N-C-C-N(+) backbone occurred. In each case, HTED had three to five mor e water molecules in its primary solvation shell than HPIP, indicating that differences in the energetics of desolvation before binding may partially explain the increased potency of HPIP as compared to HTED.