Quantum study of the structure of the active site of methylamine dehydrogenase

Abstract

AbstractIn this article we present the results of a quantum study performed on different models of the active site of methylamine dehydrogenase (MADH). This enzyme catalyzes the oxidation of methylamine to produce formaldehyde and ammonia. During the rate‐determinant step of the reaction, a proton is transferred from the methyl group of the substrate to one of the bases of the active site. We performed calculations on three different models of the active site. The number of atoms of the models ranges from 68 to 95. Minimizations and optimizations were performed at the PM3 level of theory. The energies of the optimized structures were then recalculated at the B3LYP 6‐31G(d) level. From these energies, we calculated the barriers for H+ transfer toward the putative acceptors of the proton Asp76 and Thr122. By comparing the results of different models against each other, we drew some conclusions about the role of different residues. We found that the H+ transfer from the substrate toward Thr122 requires that this residue be ionized. The estimated barrier for this ionization was found to be >19 kcal/mol. The barrier for H+ transfer from the substrate toward Asp76 is significantly smaller. Our best estimates indicate that this barrier is 9.7 kcal/mol, when the imino group of the substrate is unprotonated and 7.7 kcal/mol when it is protonated. We thoroughly discussed the agreement and disagreement of these values with the results reported in previous theoretical and experimental studies. © 2005 Wiley Periodicals, Inc. Int J Quantum Chem, 2005