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Author: search.filters.author.Hansen, NielsSubject: search.filters.subject.620

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    Binding free energies for the SAMPL8 CB8 “Drugs of Abuse” challenge from umbrella sampling combined with Hamiltonian replica exchange
    (2022) Markthaler, Daniel; Kraus, Hamzeh; Hansen, Niels
    Umbrella sampling along a one-dimensional order parameter in combination with Hamiltonian replica exchange was employed to calculate the binding free energy of five guest molecules with known affinity to cucurbit[8]uril. A simple empirical approach correcting for the overestimation of the affinity by the GAFF force field was proposed and subsequently applied to the seven guest molecules of the “Drugs of Abuse” SAMPL8 challenge. Compared to the uncorrected binding free energies, the systematic error decreased but quantitative agreement with experiment was only reached for a few compounds. From a retrospective analysis a weak point of the correction term was identified.
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    Biocatalytic stereocontrolled head-to-tail cyclizations of unbiased terpenes as a tool in chemoenzymatic synthesis
    (2024) Schneider, Andreas; Lystbæk, Thomas B.; Markthaler, Daniel; Hansen, Niels; Hauer, Bernhard
    Terpene synthesis stands at the forefront of modern synthetic chemistry and represents the state-of-the-art in the chemist’s toolbox. Notwithstanding, these endeavors are inherently tied to the current availability of natural cyclic building blocks. Addressing this limitation, the stereocontrolled cyclization of abundant unbiased linear terpenes emerges as a valuable tool, which is still difficult to achieve with chemical catalysts. In this study, we showcase the remarkable capabilities of squalene-hopene cyclases (SHCs) in the chemoenzymatic synthesis of head-to-tail-fused terpenes. By combining engineered SHCs and a practical reaction setup, we generate ten chiral scaffolds with >99% ee and de , at up to decagram scale. Our mechanistic insights suggest how cyclodextrin encapsulation of terpenes may influence the performance of the membrane-bound enzyme. Moreover, we transform the chiral templates to valuable (mero)-terpenes using interdisciplinary synthetic methods, including a catalytic ring-contraction of enol-ethers facilitated by cooperative iodine/lipase catalysis.