RECOGNITION AND INTERACTION OF SMALL RINGS WITH THE RICIN A-CHAIN BINDING-SITE

Ricin A-chain is an N-glucosidase that attacks ribosomal RNA at a high ly conserved adenine residue, Our recent crystallographic studies show that not only adenine and formycin, but also pterin based rings can b ind in the active site of ricin, For a better understanding of the mea ns by which ricin recognizes adenine rings, the geometries and interac tion energies were calculated for a number of complexes between ricin and tautomeric modifications of formycin, adenine, pterin, and guanine , These were studied by molecular mechanics, semi-empirical quantum me chanics, and ab initio quantum mechanical methods, The calculations in dicate that the formycin ring binds better than adenine and pterin bet ter than formycin, a result that is consistent with the crystallograph ic data, A tautomer of pterin that is not in the low energy form in ei ther the gas phase or in aqueous solution has the best interaction wit h the enzyme, The net interaction energy, defined as the interaction e nergy calculated in vacuo between the receptor and an inhibitor minus the solvation energy of the inhibitor, provides a good prediction of t he ability of the inhibitor to bind to the receptor, The results from experimental and molecular modeling work suggest that the ricin bindin g site is not flexible and may only recognize a limited range of adeni ne-like rings. (C) 1998 Wiley-Liss, Inc.