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Dialogs with water

Simulation with molecules that change their behavior when immersed in solvents makes it possible to model new substances

It is difficult to study the behavior of molecules in a liquid phase or in solution, even if this is their natural habitat in which vital processes take place – the formation of proteins, DNA and cell membranes, for example. The problem is that when a substance is put into common solvents, like water and acetone, it has its properties altered and starts interacting, conversing with these media. A sort of dance takes shape, with constant movement that generates an enormous quantity of images to be assessed. Which of these images should we look at?

Using computer simulations and multidisciplinary methods, the Molecular Sciences group from the Institute of Physics of the University of São Paulo (Ifusp) answers this question with results that make industrial processes move forward, in particular for medicines and cosmetics. The researchers concluded, first, that those who see the substance on its own and then immersed in liquids observe two completely different situations. The research is helping to understand better the deviations in the behavior of the molecules. In almost five years, the group analyzed the behavior of some 20 substances. “Our most recent application was with beta-carotene: its interaction with solvents is special”, says Sylvio Canuto, the coordinator of the team.

Heat and rhythm
A hydrocarbon made up of single and double links between carbon atoms and found in vegetable foods – carrots, mangoes and papaya, among others,beta-carotene is one of the precursors of vitamin A, which is directly linked to good vision. Hard and inflexible, this molecule is also apolar – it has littler capacity for attracting and altering other molecules. And that is a challenge for the researches. The last characteristic is however only manifested when beta-carotene is analyzed in isolation. In liquid, the picture changes, because density is high and movement intense.

In the dispute for spaces, constantly provoked by the presence of the solvent, the beta-carotene responds to the stimuli by developing induced polarity: it starts to interact with the molecules of the liquid, in particular those that are closer to it. This dance can be comparable with a bolero, samba or hard rock, depending on the temperature. Called the Van der Waals force, it is an interaction that causes changes in the levels of energy – the layers or orbits where the electrons are distributed. In isolation, the beta-carotene molecule has hypothetical levels of energy A, B and C; in the solvent, these levels change to A1, B1 and C1.

Who decides what these new levels are may also define precisely the quantity of energy that the electrons need to jump from one range to another. In the case of carotene, the researchers indicated the amounts of energy of the first absorption band in the four solvents in which it was assessed – methanol, isopentane, acetone and acetonitrile. “The results that we achieved are in full agreement with the experimental work”, explains Kaline Coutinho, a professor at the University of Mogi das Cruzes who is taking part in the group. “Until now, no other method had succeeded in carrying out these calculations in as accurately as ours”.

Canuto is also commemorating. “Now we have a safe and reliable model for analysis, which can be applied to other molecules with similar properties”. The studies are at the initial stages of observations to understand what is happening, but, in the long term, the analysis of molecules in liquids should bring great contributions to the medicine and cosmetics industries, among others. For example: synthesizing medicines with the prospects of interfering in their make-up, to eliminate possible effects of undesirable side effects. The same goes for products of cosmetics.

RPG and casinos
The study of what happens with molecules immersed in solvents gained strength after the Second World War, but in the last 15 years the development of observation programs led to a leap in quality. The group from USP uses tools of information technology as if it were in front of a RPG (Role Playing Game): in this game of playing roles which for years has been fascinating adolescents all around the world, the participants embody imaginary characters to act in the face of concrete problems and to presents answers. Instead of idealized creatures, the researchers deal with molecules, which have their dances and interactions simulated by a computer, in a way that is as close as possible to reality.

The computer programs that the group is developing are the instrument for observing the molecules and guarantee a peep into the chaotic that is being manifested. Through the photographs that they produce, the distance between the atoms can be found out, the modifications that take place in the energy levels, the quantity of layers of molecules and in which way they move can be assessed, besides obtaining statistical data and graphs of each simulation.

Difficult calculations
There is, however, a long way to go before arriving at this stage. After all, liquids do not have a defined geometrical form and may take on an infinity of shapes and positions – a characterstic called statistical behavior. Add to this the fact that the group is investing in multidisciplinary analysis: the reading of what goes on in the simulations demands the use of quantum physics (which studies matter on the smallest scale) and of statistical physics (which deals with the average behavior of the system), besides seeking support in the chemical and biological processes involved.

The intersection between statistical behavior and multidisciplinarity has brought a crucial challenge: if, because of the solvents, millions of scenes and configurations are generated, how can quantum calculations that take weeks be carried out? Should they not solve this dilemma, physicists could be in an untenable situation, due to the quantity of information obtained and to the time needed to assess it. The answer they wanted emerged from the statistical analysis of the data, which selects only the relevant images, generated using what is called the Monte Carlo technique – a reference to the city of casinos, where probability dictates the rules.

The selection of the best moments ensures a huge gain in time, without loss of quality or confidence in the results. One example: In the case of another molecule studied, benzene, the researchers did the calculations with 10,000 molecular configurations and afterwards repeated them using only 40 of them. “The results were the same”, Canuto guarantees. Accordingly, the simulations became far nimbler – a calculation that at the beginning of the 90’s would take up to 40 hours is now ready in less than one minute.

The group observed and detailed another phenomenon that occurs with some substances: the hydrophobic effect, or the inability of some molecules to mix with water. In this case, they worked with benzene and developed a model that serves for other hydrophobic molecules. Also a hydrocarbon, made up of six atoms of hydrogen and six of carbon, linked together in the shape of a hexagon, benzene is used on a large scale in the production of resins, plastics, lubricants and detergents, amongst other products, besides being added to diesel oil and to gasoline to improve their characteristics.

In this case, the group split up the observation process into two stages. First, it analyzed the interactions in the gaseous phase in two distinct situations: the first situation included one molecule of water and another of benzene; in the second, two molecules of benzene were used. The researchers went on noting down what happened, without there yet being any interference with liquid, to establish afterwards comparisons and to see what changed.

In the second stage, they assessed one and then two molecules of benzene, surrounded by 400 molecules of water. In the two cases, it was noted that in the region closest to the benzene a protective cage was formed, called a chlatrate. Made up of molecules of water connected by hydrogen links, this insulating capsule prevents interaction between the media. It is an evident manifestation of the hydrophobic effect. Canuto reveals: “In comparison with the gaseous phase, the interaction between benzene and water, when mixed, was reduced by 80%. On the other hand, we noticed that the interaction between the benzenes in the chlatrate is three times more than that to be found in gas, and twice as much as there is in a liquid made up purely of benzenes”.

Putting it plainly, it is possible to state that, in the presence of water, the molecules of benzene prefer to strengthen their relationship and to talk among themselves, leaving the rest aside – and the same happens with water. As the two parties manifest no interest in setting up a dialog, the hydrophobic effect arises. “We managed to quantify some of its aspects”, Canuto adds. The studies carried out by the group between 1999 and 2002 gave rise to 27 articles in international magazines and 11 dissertations for master’s and doctor’s degrees and for scientific initiation projects.

Without trial and error
Besides beta-carotene and benzene, the group analyzed complexes of guanine and cytosine (elementary parts of DNA) in water; pyridine, pyrimidine and pyrazine (nitrogenous based molecules) in various solvents; and families of ketones and dyes in various liquids. Interchange with other institutions and groups is continuous. In Brazil, researchers from the Institute of Chemistry of the Federal University of São Carlos (UFSCar), the Institute of Chemistry at USP and the Institute of Chemistry of the State University of Campinas (Unicamp) are also working with computer simulation involving liquids. “They are all doing science of the best quality”, Canuto points out. “The difference is that we started to apply quantum mechanics to liquids, and we may perhaps be the only Brazilian group to work from this perspective”.

For Canuto, partnerships with chemical and pharmaceutical industries would be healthy, in particular because, at the moment, as a result of the knowledge and the competence they have developed, universities can establish a stable and symmetrical relationship – and not one of dependence. After all, the idea of designing molecules to take on given behaviors, eliminating costs and boosting benefits, is proving to be increasingly feasible.

Kaline Coutinho recalls that experiments are now being done with various solvents, until arriving at the correct one for each kind of situation. “There is still test after test until arriving at the ideal one”, the researcher comments. That is not the way that one wants to work. “We will be able to eliminate this method of trial and error and change directions, now indicating the best kind of solvent for each purpose”.

In this process of molecular modeling, quantum mechanics occupies a prominent position. Using a precise knowledge of the interactions that the molecules establish with the solvents, they can be modified to bring about, for example, less toxic and more efficient medicines.

Having worked for over 25 years in the area and impassioned by the idea that, in the last instance, biological mechanisms depend on physical interactions between molecules, Canuto is satisfied with the results. He recalls, however, that success will only be complete if the multidisciplinary perspective is maintained, which the group emphasizes, and to which he attributes the breadth of the results. “The electron doesn’t say: ‘Now I am behaving on the basis of physical principles, now I have changed to chemistry'”, the researcher comments. “It simply behaves, and challenges us to understand this behavior”.

The project
Electronic Structure of Molecular Liquids (nº 98/09933-8); Modality
Thematic project; Coordinator Sylvio Roberto Accioly Canuto – Institute of Physics of the University of São Paulo; Investment R$ 311,181.39