In this study, mechanisms of phosphodiester hydrolysis catalyzed by six di- and tetravalent metal-cyclen ( M-C ) complexes ( Zn-C, Cu-C, Co-C, Ce-C, Zr-C and Ti-C ) have been investigated using DFT calculations. The activities of these complexes were studied using three distinct mechanisms: (1) direct attack ( DA ), (2) catalyst-assisted ( CA ), and (3) water-assisted ( WA ). All divalent metal complexes ( Zn-C, Cu-C and Co-C ) coordinated to the BNPP substrate in a monodentate fashion and activated its scissile phosphoester bond. However, all tetravalent metal complexes ( Ce-C, Zr-C , and Ti-C ) interacted with BNPP in a bidentate manner and strengthened this bond. The DA mechanism was energetically the most feasible for all divalent M-C complexes, while the WA mechanism was favored by the tetravalent complexes, except Ce-C . The divalent complexes were found to be more reactive than their tetravalent counterparts. Zn-C catalyzed the hydrolysis with the lowest barrier among all M-C complexes, while Ti-C was the most reactive tetravalent complex. The activities of Ce-C and Zr-C , except Ti-C , were improved with an increase in the coordination number of the metal ion. The structural and mechanistic information provided in this study will be very helpful in the development of more efficient metal complexes for this critical reaction.

Classical molecular dynamics simulations are a versatile tool in the study of biomolecular systems, but they usually rely on a fixed bonding topology, precluding the explicit simulation of chemical reactivity. Certain modifications can permit the modeling of reactions. One such method, multiscale reactive molecular dynamics, makes use of a linear combination approach to describe condensed-phase free energy surfaces of reactive processes of biological interest. Before these simulations can be performed, models of the reactive moieties must first be parametrized using electronic structure data. A recent study demonstrated that gas-phase electronic structure data can be used to derive parameters for glutamate and lysine which reproduce experimental pK a values in both bulk water and the staphylococcal nuclease protein with remarkable accuracy and transferability between the water and protein environments. In this work, we first present a new model for aspartate derived in similar fashion and demonstrate that it too produces accurate pK a values in both bulk and protein contexts. We also describe a modification to the prior methodology, involving refitting some of the classical force field parameters to density functional theory calculations, which improves the transferability of the existing glutamate model. Finally and most importantly, this reactive molecular dynamics approach, based on rigorous statistical mechanics, allows one to specifically analyze the fundamental physical causes for the marked pK a shift of both aspartate and glutamate between bulk water and protein and also to demonstrate that local steric and electrostatic effects largely explain the observed differences.

This paper describes the synthesis, characterization, and modeling of a series of molecules having four protein domains attached to a central core. The molecules were assembled with the “megamolecule” strategy, wherein enzymes react with their covalent inhibitors that are substituted on a linker. Three linkers were synthesized, where each had four oligo­(ethylene glycol)-based arms terminated in a para-nitrophenyl phosphonate group that is a covalent inhibitor for cutinase. This enzyme is a serine hydrolase and reacts efficiently with the phosphonate to give a new ester linkage at the Ser-120 residue in the active site of the enzyme. Negative-stain transmission electron microscopy (TEM) images confirmed the architecture of the four-armed megamolecules. These cutinase tetramers were also characterized by X-ray crystallography, which confirmed the active-site serine-phosphonate linkage by electron-density maps. Molecular dynamics simulations of the tetracutinase megamolecules using three different force field setups were performed and compared with the TEM observations. Using the Amberff99SB-disp + pH7 force field, the two-dimensional projection distances of the megamolecules were found to agree with the measured dimensions from TEM. The study described here, which combines high-resolution characterization with molecular dynamics simulations, will lead to a comprehensive understanding of the molecular structures and dynamics for this new class of molecules.

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In this computational study, we have combined molecular docking and molecular dynamics (MD) simulation techniques to explore interactions of monomeric and aggregated forms of Alzheimer’s amyloid beta (Aβ40) with seven chemically distinct heparin derived glycoaminoglycans (GAGs) referred to as ADC, SDC, DC, V1, V2, V3, and V4. The docking procedure proposed two major binding sites, i.e., one present at the top of the fibril (site A), and the other located in the hairpin region (site B). Due to its position, site B offers an interesting target to design molecules with anti-aggregation properties. Our results predicted that out of seven GAGs, only three of them (ADC, SDC, and DC) bind to site B. The identification of these molecules can advance our efforts to develop therapeutic interventions for this deadly disease.