Theoretical chemists on cover of ChemComm

VU Theoretical chemists Trevor A Hamlin and Matthias Bickelhaupt have revealed how magnesium ions lower the reaction barrier in enzymatic triphosphate hydrolysis (a key step in DNA replication and other reactions that are vital to life), using quantum chemical methods.

04/19/2018 | 1:53 PM

The work of Trevor A. Hamlin and Matthias Bickelhaupt of the Department of Theoretical Chemistry has been published in ChemComm, the flagship communications journal of the Royal Society of Chemistry (Cambridge), where it was awarded by the editor with an appearance on the cover.

DNA replication
Triphosphate hydrolysis is ubiquitous in biochemistry and serves a primary role in DNA replication but also in biochemical energy storage and transfer. DNA replication is key to expressing our genetic information, and to passing it on to the next generation: they belong to the fundamental chemical reactions of life.

Magnesium ions play a pivotal role in this reaction, speeding up an otherwise exceptionally slow process. The physical mechanism through which the ions achieve their effect was still poorly understood.

Two mechanisms
Now, the team of researchers led by Hamlin and Bickelhaupt has, for the first time, fully uncovered the enzymatic role of the magnesium ions, disentangled from the remaining enzyme environment, on this SN2@P reaction. They have demonstrated how magnesium ions lower the barrier of the enzymatic triphosphate hydrolysis through two distinct mechanisms: (a) weakening of the leaving-group bond, thereby decreasing activation strain; and (b) an enhancement of the electrophilicity of the triphosphate PPP substrate, thereby stabilizing the interaction with the nucleophile.

These insights have emerged from analyses using the research team’s activation strain model of chemical reactivity.