The structure of N δ -( N ′-sulfodiaminophosphinyl)- l -ornithine and its binding to ornithine transcarbamoylase: A quantum chemical study

Abstract

The structure of N i -( N '-Sulfodiaminophosphinyl)- l -ornithine (PSOrn) in complex with the enzyme ornithine transcarbamoylase (OTCase) was recently characterised by Langley et al. [D.B. Langley, M.D. Templeton, B.A. Fields, R.E. Mitchell and C.A. Collyer, J. Biol. Chem., 275 (2000) 20012] using X-ray diffraction techniques. In this work, the interaction of PSOrn with the arginine residues of OTCase is modelled using density functional theory, with an emphasis on characterising the mechanism of binding between PSOrn, an inhibitor, and the enzyme. For the purposes of this study, the interaction of PSO, an analogue of PSOrn (obtained by replacing a (CH 2 ) 3 CH( CO 2 m )( NH 3 + ) side chain by methyl) with one and two arginine (Arg) molecules are investigated. The PSO > (Arg) 2 trimer is found to be strongly bound, by ∼171 kJ mol m 1 , due to the presence of four hydrogen bonds in addition to a large ionic interaction between a dinegative PSO 2 m and protonated arginines. The computed geometry is consistent with the X-ray structure and the large binding energy is consistent with the observation that PSOrn is a powerful inhibitor. Furthermore, in agreement with the proposals of Langley et al. , the most stable bound form of PSO is found to be an imino type tautomer. The population analyses that were carried out on PSO suggest that PN, PO, SN and SO bonds, as in a range of other systems, are generally either single or semipolar bonds.

Keywords:

• N δ -( N ′-Sulfodiaminophosphinyl)- l -ornithine
• Psorn
• Phaseolotoxin
• Enzyme/inhibitor Interactions
• Hydrogen Bonding
• B3lyp Dft Computations