It opens the mind. This is the response of Jana Selent, researcher of the IMIM and UPF Pharmacoinformatics group, when asked what can be achieved by the simulations programmed by her team using state-of-the-art computational microscopes. Computer biosimulations, the latest technologies in the field of biocomputation, help to see things that we would not normally be able to see, to enter a world at a level of resolution and approximation that is not possible using experimental methods, revealing the why and how of biomolecules such as proteins, whose life at the atomic level we can only guess at. Simulation makes it possible to visualize and predict trajectories, bonds, successes and failures at the level of connection and transmission and helps to design new drugs or improve existing ones. Simulation connects prior knowledge and results that cannot be explained and brings everything into focus.

 

Simulation makes it possible to visualize and predict trajectories, bonds, successes and failures at the level of connection and transmission and helps to design new drugs or improve existing ones.

 

Major questions about connectivity in the human brain

Making sense of existing isolate knowledge of the dynamics of bonds between elements of the brain membrane that are involved in some diseases of the nervous system thanks to simulation is what has been achieved by the researchers of the IMIM Research Programme on Biomedical Informatics, in collaboration with Pompeu Fabra University and researchers of the University of Tampere and Universitat de Barcelona. The work is based on the expertise of the IMIM research group in the study of G proteins and their coupled receptors (GPCR), which are found in the membranes of neurons, in the brain, and which respond to extracellular stimuli such as light or odors and function as signal transducers, transmitting a message to the interior of the cell.

Molecular simulation using computational microscopes has been programmed to imitate natural processes of interrelation between the receptors of the normal brain in order to be able to compare them with processes in people with diseases such as Parkinson and Alzheimer. The final, exciting reason is to be able to help people by improving these transmissions when they do not work normally. The big question is knowing what is happening at the atomic level when the GPCR, neurotransmitter receptors such as adenosine and dopamine, are called on to generate a signal in the cells to react to stimuli, because we already know what a process is and about the completely different responses when there are disorders.

 

The relationship between proteins and fatty acids

Which elements are involved in these cases, as conditioning factors or facilitators of this reception and connectivity? This is the first study to demonstrate the role of polyunsaturated lipids in the membrane as regulators of the speed of bonding between receptors. It was based on publications by different groups that agree that the polyunsaturated lipid profile in the brains of people with diseases such as Alzheimer is lower than in healthy people. This was the inspiration to determine more fully their role and how it is affected by the quantity of fatty acids in the membrane. The simulation visualizes a complex and fascinating interaction: the omega-3 fatty acids in the neuron membrane interact with the GPCR receptors and can be seen to form islands that act as platforms for signalling. The fatty acids must be there in equilibrium to facilitate fluid communications. If the membrane does not have sufficient polyunsaturated such as DHA (docosahexanoic acid), as is the case in patients with disease, we find fewer islands; dopamine and adenosine cannot transmit signals to the interior of the cell and communication is affected.

 

How can we get the fatty acids into place?

This discovery opens the door to new experiments that can make use of this knowledge. A new challenge is to propose experiments, as is already being done with mice in collaboration with Hospital de Bellvitge, which attempt to improve the lipid profile in the brain membrane with a diet rich in these omega-3 acids. This will make it possible to evaluate the quantity that reaches the membrane, as the brain has a highly selective barrier, while determining whether symptoms improve. It also raises the possibility of analyzing other problems regarding the synthesis or absorption of omega-3 fatty acids in these patients. Furthermore, we could study other therapeutic strategies for designing new lipids with a modulating effect on binding speed or study whether the lipids may play a similar role in modulating the behavior of other receptors, etc. As usually happens with the results of simulations, new hypotheses appear and we take steps forward. Having seen the mechanism of action of these biomolecules and revealing their key role in the connectivity of the cell membrane through simulation, a whole host of new possibilities arise to allow us to continue working.

 

 

Reference article

Ramon Guixà-González, Matti Javanainen, Maricel Gómez-Soler, Begoña Cordobilla, Joan Carles Domingo, Ferran Sanz, Manuel Pastor, Francisco Ciruela, Hector Martinez-Seara, Jana Selent. Membrane omega-3 fatty acids modulate the oligomerisation kinetics of adenosine A2A and dopamine D2 receptors Membrane levels of docosahexaenoic acid. 2016 Scientific Reports 6:19839.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4726318/