Modeling Molecular Interactions in Water: From Pairwise to Many-Body Potential Energy Functions.

Almost 50 years have passed from the first computer simulations of water, and a large number of molecular models have been proposed since then to elucidate the unique behavior of water across different phases. In this article, we review the recent progress in the development of analytical potential energy functions that aim at correctly representing many-body effects. Starting from the many-body expansion of the interaction energy, specific focus is on different classes of potential energy functions built upon a hierarchy of approximations and on their ability to accurately reproduce reference data obtained from state-of-the-art electronic structure calculations and experimental measurements. We show that most recent potential energy functions, which include explicit short-range representations of two-body and three-body effects along with a physically correct description of many-body effects at all distances, predict the properties of water from the gas to the condensed phase with unprecedented accuracy, thus opening the door to the long-sought "universal model" capable of describing the behavior of water under different conditions and in different environments

What is the Catalytic Mechanism of Enzymatic Histone N-Methyl Arginine Demethylation and Can It be Influenced by an External Electric Field?

Arginine methylation is an important mechanism of epigenetic regulation. Some Fe(II) and 2-oxoglutarate dependent Jumonji-C (JmjC) Nϵ-methyl lysine histone demethylases also have N-methyl arginine demethylase activity. We report combined molecular dynamic (MD) and Quantum Mechanical/Molecular Mechanical (QM/MM) studies on the mechanism of N-methyl arginine demethylation by human KDM4E and compare the results with those reported for N-methyl lysine demethylation by KDM4A. At the KDM4E active site, Glu191, Asn291, and Ser197 form a conserved scaffold that restricts substrate dynamics; substrate binding is also mediated by an out of active site hydrogen-bond between the substrate Ser1 and Tyr178. The calculations imply that in either C−H or N−H potential bond cleaving pathways for hydrogen atom transfer (HAT) during N-methyl arginine demethylation, electron transfer occurs via a σ-channel; the transition state for the N−H pathway is ∼10 kcal/mol higher than for the C−H pathway due to the higher bond dissociation energy of the N−H bond. The results of applying external electric fields (EEFs) reveal EEFs with positive field strengths parallel to the Fe=O bond have a significant barrier-lowering effect on the C−H pathway, by contrast, such EEFs inhibit the N−H activation rate. The overall results imply that KDM4 catalyzed N-methyl arginine demethylation and N-methyl lysine demethylation occur via similar C−H abstraction and rebound mechanisms leading to methyl group hydroxylation, though there are differences in the interactions leading to productive binding of intermediates