Experimental methods have certain limits and there are times when nature briefly switches off the lights on scene to hide its tricks. One of these moments takes place during chemical reactions. All chemical reactions go through a sort of Limbo, a ghost-like stage between the initial reagents and the final product in which it is almost impossible to know experimentally what has occurred in the intermediate phase. A group of researchers from the Universitat Jaume I (UJI) of Castelló use techniques based on computational chemistry to theoretically model this unknown transition state and thus design compounds that either inhibit or enhance the action of biological catalysts.
A chemical reaction resembles the pass from one valley to another by way of a mountain. Valleys are stable areas, but if we attempt to go from one to the other, we need to cross an unstable point of maximum height along the way, that is, a hill. In the case of a chemical reaction, the initial and final molecules also have the features of stable structures that can be studied experimentally. To skip between them however, it is necessary to go through an unstable structure of maximum energy throughout the reaction, the hill of the chemical reaction, or in other words, its transition state.
This state is particularly interesting because biological catalysts or enzymes which accelerate chemical reactions taking place in living beings (from the transformation of food into energy to cell reproduction, among many others) do so by stabilising this unstable structure. Intervening in this transition state would allow us to stop or enhance a chemical reaction. However, this is so brief that it is impossible to know its structure in an experimental way. By means of theoretical simulations and the use of high-performance computers, researchers at the UJI have found out the way that certain chemical reactions follow, and have either suggested ways of blocking it, or proposed more efficient alternative routes.
“If we know the transition state structure, which is unstable by definition and, therefore, cannot be studied experimentally, we can then synthesise molecules that are similar to it yet chemically stable, which in other words is known as a transition state analogue”, explains Vicent Moliner, the person in charge of the research. The transition state analogue (TSA) is the molecular negative of the enzyme catalysing a certain reaction. This may then be used to block such enzyme action, by thus inhibiting an undesired chemical reaction from occurring.
“The development of this project is fundamental to improve the selectivity of drugs applied in chemical-therapeutic treatments. If we are able to know the structure of transition states in catalytic reactions involved, for example, in cell proliferation processes in tumours, we will be able to design drugs capable of stopping these reactions and preventing the spread of cancer”, explains Vicent Moliner. This principle can also be applied to other pathologies. “Among other systems, we are currently working with catechol-O-methyl transferase given its future applications in the treatment of degenerative diseases such as Parkinson’s disease. We are also working with HIV-1 IN, an enzyme that uses the HIV virus to replicate itself”, Moliner adds.
In the case of degenerative diseases, Moliner’s team has managed to define the structure of the transition state of a chemical reaction which is a key factor in the production of dopamine. The disequilibrium in the generation of this neurotransmitter is responsible for certain neurological diseases, such as Parkinson’s disease. “Knowing the structure of this reaction is a crucial step. We are now close to being able to suggest the synthesis of inhibitors that correct the disequilibrium of dopamine”, explains Vicent Moliner. The results have been published in several articles in the Journal of the American Chemical Society and in Chemical Society Reviews.
However, knowing the structure of chemical reactions is not only useful to block them, but also to propose biological catalysts for chemical reactions that we wish to accelerate. To this end, the TSA compound is introduced in a living system ( a rodent) to generate antibodies that will be macromolecules to complement TSA, that is, something like its photograph negative. Since antibodies are complementary to TSA, they can then be used as catalysts as they stabilise the transition state of the chemical reaction. These compounds are known as catalytic antibodies (CA).
“Nevertheless, catalytic antibodies that are generated so (germline CA) do not work very well as catalysts, so an improvement is sought for by means of selective mutations in the lab through trial and error tests (matured CA). However, this improvement is not very effective, and the work we have been carrying out in our group allows us to rationally determine what mutations should be tested in the lab to enhance the catalytic activity of CA”, Moliner points out. “These new molecules are particularly interesting in processes for which no catalyst exists to catalyse them, or for those processes in which the enzyme is not functioning properly”, Moliner indicates. These results have recently been published in the journal Angewandte Chemie.
Hugo Cerdà | alfa
The big clean up after stress
25.05.2018 | Julius-Maximilians-Universität Würzburg
Complementing conventional antibiotics
24.05.2018 | Goethe-Universität Frankfurt am Main
A research team led by physicists at the Technical University of Munich (TUM) has developed molecular nanoswitches that can be toggled between two structurally different states using an applied voltage. They can serve as the basis for a pioneering class of devices that could replace silicon-based components with organic molecules.
The development of new electronic technologies drives the incessant reduction of functional component sizes. In the context of an international collaborative...
At the LASYS 2018, from June 5th to 7th, the Laser Zentrum Hannover e.V. (LZH) will be showcasing processes for the laser material processing of tomorrow in hall 4 at stand 4E75. With blown bomb shells the LZH will present first results of a research project on civil security.
At this year's LASYS, the LZH will exhibit light-based processes such as cutting, welding, ablation and structuring as well as additive manufacturing for...
There are videos on the internet that can make one marvel at technology. For example, a smartphone is casually bent around the arm or a thin-film display is rolled in all directions and with almost every diameter. From the user's point of view, this looks fantastic. From a professional point of view, however, the question arises: Is that already possible?
At Display Week 2018, scientists from the Fraunhofer Institute for Applied Polymer Research IAP will be demonstrating today’s technological possibilities and...
So-called quantum many-body scars allow quantum systems to stay out of equilibrium much longer, explaining experiment | Study published in Nature Physics
Recently, researchers from Harvard and MIT succeeded in trapping a record 53 atoms and individually controlling their quantum state, realizing what is called a...
The historic first detection of gravitational waves from colliding black holes far outside our galaxy opened a new window to understanding the universe. A...
02.05.2018 | Event News
13.04.2018 | Event News
12.04.2018 | Event News
24.05.2018 | Ecology, The Environment and Conservation
24.05.2018 | Medical Engineering
24.05.2018 | Physics and Astronomy