Molecular Dynamics Study of the Active Site of Methylamine Dehydrogenase

We have obtained AMBER94 force-field parameters for the TTQ cofactor of the enzyme methylamine
dehydrogenase (MADH). This enzyme catalyzes the oxidation of methylamine to produce formaldehyde and
ammonia. In the rate-determining step of the catalyzed reaction, a proton is transferred from the methyl
group of the substrate to residue Asp76. We used the new parameters to perform molecular dynamics
simulations of MADH in order to characterize the dynamics of the active site prior to the proton-transfer
step. We found that only one of the oxygen atoms of Asp76 can act as an acceptor of the proton. The other
oxygen interacts with Thr122 via a strong hydrogen bond. In contrast, because of the rotation the methyl
group of the substrate, the three methyl hydrogen atoms are alternately in position to be transferred. The
distance that the proton has to travel presents a broad distribution with a peak between 1.0 and 1.1 Å and
reaches values as short as 0.8 Å. The fluctuation of the distance between the donor and the acceptor has the
largest frequency component at 50 cm-1, but the spectrum presents a rich structure between 10 and 400
cm-1. The more important peaks appear below 250 cm-1.