Experimental and ab initio calculated structures of 2-aminoindane-2-phosphonic acid, a potent inhibitor of phenylalanine ammonia-lyase, and theoretical studies of its binding to the model enzyme structure

Abstract

The structure of 2-aminoindane-2-phosphonic acid (AIP) was studied using X-ray crystallography, NMR spectroscopy, molecular modelling, IR spectroscopy, and potentiometric titration. In the solid state, a thermodynamically stable conformer of AIP is one in which the phosphonic group occupies the equatorial position and the amino group the axial position. The NMR data suggest that fast equilibrium in solution between the two conformers of AIP is significantly shifted toward the equatorial conformer (EC). Both solid state studies, that is X-ray analysis and IR spectroscopy of AIP, revealed the presence of hydrogen-bonded water. Ab initio calculations in the gas phase indicate only a small barrier between the two possible conformations of AIP. Binding studies of both conformers, in various protonation states, to the model of the phenylalanine ammonia-lyase structure suggest that only the axial phosphonic group conformer is docked specifically. Indications from modelling are that phenylalanine ammonia-lyase binds AIP's conformer with higher specificity and that the molecular reorganisation required can be responsible for the experimentally observed time-dependent inhibition.