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Enzyme Kinetics and Drugs as Enzyme Inhibitors
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Allosteric regulation (or control) means the influence of an effector molecule on an enzyme and plays a role in cell signaling (long-range allosteric effects); it binds at a site other than the enzyme’s active site, the allosteric site. This is often accompanied by conformational changes involving protein dynamics. Effector molecules either cause positive allosteric modulation (allosteric activation) or negative allosteric modulation (allosteric inhibition) and are in a broader sense of importance for conformational perturbations on cellular functions and disease states; in other words the allosteric change in one protein may affect the behavior of other proteins downstream. Non-competitive inhibition always means allosteric inhibition but not all allosteric inhibitors act non-competitive. For models explaining the allosteric effect see Monod et al. (1965; concerted model) and Koshland et al. (1966, sequential model).
REDAN: relative entropy-based dynamical allosteric network model
Published in Molecular Physics, 2019
In REDAN model, each amino acid residue is considered as a node, and connection between any node pair is considered as an edge. The change of distance distribution between any node pair can be calculated using relative entropy method and used as the weight for the corresponding edge. These weights quantitatively measure the response of protein dynamics upon perturbation and could be used to characterise allostery induced by the same perturbation. Therefore, this network model could quantitatively describe protein allosteric effects from the perspective of structural biology and population shifting. Higher relative entropy indicates significant allosteric effect or larger distribution shift due to perturbations. Using this allosteric network model, we can quantitatively compare allosteric effects upon perturbation with minimum structural information loss.
New mechanistic insights into the Claisen rearrangement of chorismate – a Unified Reaction Valley Approach study
Published in Molecular Physics, 2019
Marek Freindorf, Yunwen Tao, Daniel Sethio, Dieter Cremer, Elfi Kraka
Over decades the modelling of chemical reactions has proved that simplifications of the physical reality are an important tool to guarantee progress in elucidating the reaction mechanism. Clearly, the importance of free-energy landscapes for enzyme catalysis [67] is non-disputable, but in view of the difficulties of evaluating a free-energy surface for a complex enzymatic reaction and overemphasising the protein dynamics as key factor for catalysis, Warshel [68] has pointed out that there has not yet been any study that consistently established a connection between an enzyme's conformational dynamics and a significant increase in the catalytic contribution of the chemical step. He advocates that mechanistic insights can also be gained by the investigation of the potential energy surface describing enzyme and substrate interactions under environmental influences. This holds in particular if the reaction under study is not predominantly entropy driven, which applies to the chorismate rearrangement [69] and if one is primarily interested in the electronic structure changes that drive the reaction mechanism. Following this path, we have provided in many investigations sufficient evidence that the analysis of an energetically preferred reaction path can be generalised to a large extent, providing detailed insights into the mechanism of families of reactions, stretching from organic reactions to homogenous catalysis [70–76]. In this work, we will provide the proof of concept that this also holds for enzymatic reactions.
Molecular theory of the genetic code
Published in Molecular Physics, 2018
The non-covalent traits of folded proteins do constitute a coherent and integrated functional unit, whose inner workings is an elaborate apparatus that feeds on teleonomy, eventually leading to the primitive cell and to wit the central nervous system of living beings. The applied mathematician George Hall, noted in his Recollection and Reflections, published in a Special Issue of the International Journal of Quantum Chemistry to his honour [23], from earlier studies of his research group, on phenethylalamine and amphetamine [24], ‘that their protonated forms had the side chain folded over the benzene ring’ and concluded that ‘this folding helps protect the charge during the motion of the molecule through the liquid, and so could have important implications for the biological action of these molecules’. Protein dynamics does require a new physical principle that accounts for its non-covalent details.