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
Nanoparticle Exposure Can Awaken Dormant Viruses in the Lungs
16.01.2017 | Helmholtz Zentrum München - Deutsches Forschungszentrum für Gesundheit und Umwelt
Cholera bacteria infect more effectively with a simple twist of shape
13.01.2017 | Princeton University
Among the general public, solar thermal energy is currently associated with dark blue, rectangular collectors on building roofs. Technologies are needed for aesthetically high quality architecture which offer the architect more room for manoeuvre when it comes to low- and plus-energy buildings. With the “ArKol” project, researchers at Fraunhofer ISE together with partners are currently developing two façade collectors for solar thermal energy generation, which permit a high degree of design flexibility: a strip collector for opaque façade sections and a solar thermal blind for transparent sections. The current state of the two developments will be presented at the BAU 2017 trade fair.
As part of the “ArKol – development of architecturally highly integrated façade collectors with heat pipes” project, Fraunhofer ISE together with its partners...
At TU Wien, an alternative for resource intensive formwork for the construction of concrete domes was developed. It is now used in a test dome for the Austrian Federal Railways Infrastructure (ÖBB Infrastruktur).
Concrete shells are efficient structures, but not very resource efficient. The formwork for the construction of concrete domes alone requires a high amount of...
Many pathogens use certain sugar compounds from their host to help conceal themselves against the immune system. Scientists at the University of Bonn have now, in cooperation with researchers at the University of York in the United Kingdom, analyzed the dynamics of a bacterial molecule that is involved in this process. They demonstrate that the protein grabs onto the sugar molecule with a Pac Man-like chewing motion and holds it until it can be used. Their results could help design therapeutics that could make the protein poorer at grabbing and holding and hence compromise the pathogen in the host. The study has now been published in “Biophysical Journal”.
The cells of the mouth, nose and intestinal mucosa produce large quantities of a chemical called sialic acid. Many bacteria possess a special transport system...
UMD, NOAA collaboration demonstrates suitability of in-orbit datasets for weather satellite calibration
"Traffic and weather, together on the hour!" blasts your local radio station, while your smartphone knows the weather halfway across the world. A network of...
Fiber-reinforced plastics (FRP) are frequently used in the aeronautic and automobile industry. However, the repair of workpieces made of these composite materials is often less profitable than exchanging the part. In order to increase the lifetime of FRP parts and to make them more eco-efficient, the Laser Zentrum Hannover e.V. (LZH) and the Apodius GmbH want to combine a new measuring device for fiber layer orientation with an innovative laser-based repair process.
Defects in FRP pieces may be production or operation-related. Whether or not repair is cost-effective depends on the geometry of the defective area, the tools...
10.01.2017 | Event News
09.01.2017 | Event News
05.01.2017 | Event News
16.01.2017 | Trade Fair News
16.01.2017 | Automotive Engineering
16.01.2017 | Life Sciences