Abstract
In this study, molecular dynamics (MD) and docking simulations were carried out on the crystal structure of Neisseria Gonorrhoeae RsmE aiming at free energy of binding estimation (ΔG(binding)) of the methyl transfer substrate S-adenosylmethionine (SAM), as well as its homocysteine precursor S-adenosylhomocysteine (SAH). The mechanistic insight gained was generalized in view of existing homology to two other crystal structures of RsmE from Escherichia coli and Aquifex aeolicus. As a proof of concept, the crystal poses of SAM and SAH were reproduced reflecting a more general pattern of molecular interaction for bacterial RsmEs. Our results suggest that a distinct set of conserved residues on loop segments between β12, α6, and Met169 are interacting with SAM and SAH across these bacterial methyltransferases. Comparing molecular movements over time (MD trajectories) between Neisseria gonorrhoeae RsmE alone or in the presence of SAH revealed a hitherto unknown gatekeeper mechanism by two isoleucine residues, Ile171 and Ile219. The proposed gating allows switching from an open to a closed state, mimicking a double latch lock. Additionally, two key residues, Arg221 and Thr222, were identified to assist the exit mechanism of SAH, which could not be observed in the crystal structures. To the best of our knowledge, this study describes for the first time a general catalytic mechanism of bacterial RsmE on theoretical ground.