The importance of substrate positioning

Nonheme iron halogenases, such as SyrB2, WelO5, and BesD, halogenate unactivated carbon atoms of diverse substrates at ambient conditions with exquisite selectivity seldom matched by nonbiological catalysts. Using experimentally guided molecular dynamics (MD) simulations augmented with multiscale (i.e., quantum mechanics/molecular mechanics) simulations of substrate-bound complexes of BesD and WelO5, we investigate substrate/active-site dynamics that enable selective halogenation. Our simulations reveal that active-site configurational isomerization is necessary in WelO5 to attain a substrate/active-site geometry consistent with its observed chemo- and regioselectivity. Conversely, a slight reorientation of the substrate from its crystal structure position is sufficient to enable regioselective chlorination in BesD without the need to invoke active-site isomerization. We observe very different patterns of substrate–protein interactions for these two enzymes, and we relate the nature of these interactions to the distinct substrates. For BesD, we resolve the uncertainty around the mechanistic relevance of Asn219. Our simulations reveal that the optimum substrate/active-site geometry also outweighs the interactions between the metal-oxo and the protein environment in facilitating the required chemoselectivity in halogenases. Our work highlights how different substrate-dependent strategies are used to accomplish selectivity-promoting proximity in halogenases.

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About Us

The Kulik group focuses on the development and application of new electronic structure methods and atomistic simulations tools in the broad area of catalysis.

Our Interests

We are interested in transition metal chemistry, with applications from biological systems (i.e. enzymes) to nonbiological applications in surface science and molecular catalysis.

Our Focus

A key focus of our group is to understand mechanistic features of complex catalysts and to facilitate and develop tools for computationally driven design.

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