Researchers at the Frankfurt Institute for Advanced Studies (FIAS) use computer simulations to show how proteins facilitate the crossing of membranes. This can be an important path for drugs to penetrate into cells, a requirement for the treatment of tumours or autoimmune diseases.

The cell membrane separates the cell from its surrounding and acts as a barrier for particles from the environment. It prevents for instance the penetration of unwanted pathogens such as viruses or bacteria into the cell. On the other hand, vital molecules such as nutrients or drugs have to cross the cell membrane. While there are special transport systems for some molecules, others have to find their way through the cell membrane on their own. In the simplest case, the particles diffuse through the membrane, but the water-repellent fat layer in the centre of the membrane is difficult to penetrate.

Cristina Gil Herrero, a doctoral student in the research group of FIAS Fellow Sebastian Thallmair, recently discovered a way to significantly reduce this energy barrier when crossing the membrane: A membrane protein that is present for instance in muscle, fat and nerve cells, the β2-adrenoceptor, bridges the fat layer, as she showed with the help of molecular simulations. The β2-adrenoceptor reduces the barrier for two of the studied active substances by an astonishing 60 per cent. Both are drugs that relax and dilate the bronchi and are therefore used to treat lung diseases such as asthma.

The FIAS researchers use sophisticated simulation models that mimic membrane functions, for example. To do this, they assemble molecules from Lego-like building blocks. The simulations in a virtual box follow the laws of physics. The researchers noticed that the active substances cross the membrane more frequently in the presence of the β2-adrenoceptor. This aroused their curiosity to investigate the role of the β2-adrenoceptor in more detail.

The simulations illustrate how complicated it is to predict the crossing of membranes by active substances, as these interact with countless proteins in the membrane. Other proteins or lipids could also make access more difficult. The findings of the FIAS researchers can help to develop active substances that cross the barrier of cell membrane more easily and thus enter the bloodstream and possibly even cross the blood-brain barrier more quickly. 

‘With the help of computer simulations, we want to identify other proteins that show similar behaviour to the β2-adrenoceptor,’ says Sebastian Thallmair, describing the future project goals. ‘In this way, we hope to obtain a more complete picture of the complexity of the membrane crossing of active substances.’

Publication:

Cristina Gil Herrero, Sebastian Thallmair, G-Protein-Coupled Receptor Surface Creates a Favorable Pathway for Membrane Permeation of Drug Molecules, J. Phys. Chem. Lett. 15, 12643 (2024), 

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