Events & Seminars > Event Details


4:00 pm
Room 304, Chemistry Building

Evolution Through Cooperativity in the Alkaline Phosphatase Superfamily


Dr. Lynn Kamerlin
Uppsala University, Sweden

Hosted by: Professor Dave Cafiso

It is becoming clear that many, if not even most enzymes are capable of promiscuous catalytic activities. In this context, the members of the alkaline phosphatase superfamily have been popular model systems to understand enzyme selectivity and promiscuity. Modeling these enzymes is non-trivial, due both to the complexity of the inherent chemistry involved, as well as the large system size and the presence of transition metals in the catalytic site. We have performed extensive modeling of the background uncatalyzed reaction in aqueous solution, showing the competition between different mechanisms and providing a unifying framework for a decades-long controversy between computational and experimental work [1]. Following from this, we have provided a range of force-field independent parameters for a range of transition metal centers, using a non-bonded cationic dummy model [2]. In combination, this has allowed us to perform extensive empirical valence bond simulations in order to model the selectivity of two multiply promiscuous phosphonate monoester hydrolases from the alkaline phosphatase superfamily [3]. Our computational models are in agreement with key experimental observables, and are able to provide both absolute and relative activation free energies for wild-type and mutant enzymes with several different substrates. We demonstrate that the broad promiscuity of these enzymes arises out of plasticity and cooperativity in the enzyme active sites, and that this appears to be a generalized feature driving evolution not just among alkaline phosphatases but among a range of promiscuous enzymes that catalyze phosphoryl transfer reactions.


[1] F. Duarte, J. Åqvist, N. H. Williams and S. C. L. Kamerlin. J. Am. Chem. Soc. 137, 1081-1093 (2015).
[2] F. Duarte, P. Bauer, A. Barrozo, B. A. Amrein, M. Purg, J. Åqvist and S. C. L. Kamerlin. J. Phys. Chem. B. 118, 4351-4362 (2014).
[3] A. Barrozo, F. Duarte, P. Bauer, A. T. P. Carvalho and S. C. L. Kamerlin. J. Am. Chem. Soc. Just Accepted.(2015).