8 research outputs found
ENZYMES: Catalysis, Kinetics and Mechanisms
Onemarvelsattheintricate designoflivingsystems,andwecannotbutwonderhow life originated on this planet. Whether ?rst biological structures emerged as the selfreproducing genetic templates (genetics-?rst origin of life) or the metabolic universality preceded the genome and eventually integrated it (metabolism-?rst origin of life) is still a matter of hot scienti?c debate. There is growing acceptance that the RNA world came ?rst – as RNA molecules can perform both the functions of information storage and catalysis. Regardless of which view eventually gains acceptance, emergence of catalytic phenomena is at the core of biology. The last century has seen an explosive growth in our understanding of biological systems. The progression has involved successive emphasis on taxonomy ! physiology ! biochemistry ! molecular biology ! genetic engineering and ?nally the large-scale study of genomes. The ?eld of molecular biology became largely synonymous with the study of DNA – the genetic material. Molecular biology however had its beginnings in the understanding of biomolecular structure and function. Appreciationofproteins,catalyticphenomena,andthefunctionofenzymeshadalargeroleto play in the progress of modern biology
Organophosphorus Chemistry 2018
Organophosphorus chemistry is an important discipline within organic chemistry. Phosphorus compounds, such as phosphines, trialkyl phosphites, phosphine oxides (chalcogenides), phosphonates, phosphinates and >P(O)H species, etc., may be important starting materials or intermediates in syntheses. Let us mention the Wittig reaction and the related transformations, the Arbuzov- and the Pudovik reactions, the Kabachnik–Fields condensation, the Hirao reaction, the Mitsunobu reaction, etc. Other reactions, e.g., homogeneous catalytic transformations or C-C coupling reactions involve P-ligands in transition metal (Pt, Pd, etc.) complex catalysts. The synthesis of chiral organophosphorus compounds means a continuous challenge. Methods have been elaborated for the resolution of tertiary phosphine oxides and for stereoselective organophosphorus transformations. P-heterocyclic compounds, including aromatic and bridged derivatives, P-functionalized macrocycles, dendrimers and low coordinated P-fragments, are also of interest. An important segment of organophosphorus chemistry is the pool of biologically-active compounds that are searched and used as drugs, or as plant-protecting agents. The natural analogue of P-compounds may also be mentioned. Many new phosphine oxides, phosphinates, phosphonates and phosphoric esters have been described, which may find application on a broad scale. Phase transfer catalysis, ionic liquids and detergents also have connections to phosphorus chemistry. Green chemical aspects of organophosphorus chemistry (e.g., microwave-assisted syntheses, solvent-free accomplishments, optimizations, and atom-efficient syntheses) represent a dynamically developing field. Last, but not least, theoretical approaches and computational chemistry are also a strong sub-discipline within organophosphorus chemistry
A Commemorative Issue in Honor of Professor Nick Hadjiliadis: Metal Complex Interactions with Nucleic Acids and/or DNA
This Special Issue of the International Journal of Molecular Science comprises a comprehensive study on “Metal Complex Interactions with Nucleic Acids and/or DNA”. This Special Issue has been inspired by the important contribution of Prof. Nick Hadjiliadis to the field of palladium or/and platinum/nucleic acid interactions. It covers a selection of recent research and review articles in the field of metal complex interactions with nucleic acids and/or DNA. Moreover, this Special Issue on "Metal Complexes Interactions with Nucleic Acids and/or DNA" provides an overview of this increasingly diverse field, presenting recent developments and the latest research with particular emphasis on metal-based drugs and metal ion toxicity
Understanding the ATP hydrolysis mechanism in myosin using computer simulation techniques
Molecular motors are proteins that convert energy from nucleoside triphosphate hydrolysis into mechanical work. A prominent example is myosin which drives muscle contraction and a large number of additional cellular transport phenomena in all living organisms. While hydrolyzing ATP, myosin translocates along an actin filament. The catalytic cycle for ATP hydrolysis and the mechanical motor cycle are closely coupled. Although a large number of studies have been devoted to understanding the functioning of myosin since its isolation in the 19th century, the details of the chemical mechanism underlying ATP hydrolysis and its coupling to the necessary conformational changes of myosin are poorly understood. In this thesis, theoretical methods are developed and used to gain a detailed understanding of the mechanism of ATP hydrolysis in myosin and of mechanical events that immediately follow hydrolysis. Three different possible reaction routes are investigated using combined quantum mechanical and molecular mechanical (QM/MM) reaction path simulations. To include solvent screening effects in the calculations, a new approximate method "Non-Uniform Charge Scaling" (NUCS) was developed which scales the partial atomic charges on the molecular mechanical atoms so as to optimally reproduce electrostatic interaction energies between groups of protein atoms and the QM region as determined from an initial continuum solvent analysis with a simple Coulomb potential and scaled charges. NUCS is a generally-applicable method that is particularly useful in cases where an explicit treatment of water molecules is not feasible and interfaces to implicit solvent models are lacking, as is the case for current QM/MM calculations. Path optimizations were done using Hartree-Fock calculations with 3-21G(d) and 6-31G(d,p) basis sets, followed by point energy calls using density-functional theory B3LYP/6-31+G(d,p). Despite the inaccuracies inherent in this method, the present calculations currently represent the most accurate QM/MM theoretical investigation of an enzyme-catalyzed phosphoanhydride hydrolysis reaction. Possible methodological improvements for future investigations are discussed. The three pathways studied are isoenergetic within error and are thus equally likely to be populated. The 6-31G(d,p) basis set proved to be reliable in describing the geometries during the phosphate hydrolysis reactions, whereas the 3-21G(d) basis set was found to be too inaccurate. Although the energies were not sufficiently accurate, a number of structural conclusions on the mechanism of ATP hydrolysis can be drawn and related to experimental findings from isotope exchange and mutation studies. All three paths investigated follow a single-step associative-like mechanism (see movies at http://www.iwr.uni-heidelberg.de/groups/biocomp/fischer) and show very similar heavy-atom positions in the transition states regardless of the positions of the protons. In the product states, the coordination bond between Mg2+ and Ser237 (and thus the switch-1 loop) is broken. This indicates that product release is likely to occur via an exit route that opens by complete opening of the switch-1 loop ("trap door" mechanism). Moreover, the coordination distance between Mg2+ and inorganic phosphate (Pi) is extended. This indicates that after hydrolysis this bond may be completely cleaved as an early event necessary for phosphate exit. Inspired by the simulation results, a Network Hypothesis on the mechanism of ATP hydrolysis in myosin is put forward that combines previous mechanistic proposals and that is consistent with experimental data available from mutational and isotope exchange studies. Moreover, a mechanism is suggested to explain how the catalytic cycle is coupled to the motor activity of myosin