To illustratre the field of life science, here is a description of two of the projects currently using our system. The list of all current projects contains links to more project descriptions.

The behavior of lipid membranes is of great importance for a wide range of biological processes. Membranes serve as a separation of bioorganic matter and thus allow for organization of living organisms into cells and sub-cellular com- partments. Insight into cellular mechanisms is vital for a detailed understanding of malfunctions, possibly leading to severe diseases.

Generally, lipid membranes have to undergo regulated topological changes to fulfill their diverse functions. These collective membrane transformations – such as pore formation, fusion, and fission – are key to processes fundamental to all living matter, they are carefully regulated by an elaborate protein machinery, and they typically involve highly curved membrane configurations.

Thus, the description of topological changes requires to conceive them they as complex fluid materials in constant change and under the influence of thermal fluctuations.

The aim of our research is to understand – at different length scales, ranging from molecular to continuum – the role of strong curvature on the structure and collective dynamics of biological membranes. The length and time scale of these processes – micrometers and microseconds – often lie beyond the capabilities of experimental techniques. Computer simulations with varying degrees of coarse- graining help us to not only identify crucial aspects of these important and fascinating processes but also allow to access the molecular world of membranes in an intuitive way.

Figure 1: (a) Cryo-em imaging of two docked vacuoles. (b) Simulation of a fusion pore formed at the edge of the docking zone under a contact angle of 45°.

Figure 2: Protein complex tethering a vesicle to a membrane mediating fusion.

Rational drug design requires understanding of interactions that govern drug binding and drug action. In the HLRN project we use atomistic simulations to describe interactions of two molecules of interest to drug design: photo-switchable lipids, which can be used two switch on with light ion channels, and fentanyl compounds that can be used to treat pain in inflamed tissue only.

Photo-switchable lipids (Figure 1) are small synthetic molecules which change their conformation when they absorb light and undergo a reaction called photo-isomerization. Because this change in conformation associates with a change in lateral membrane pressure, photo-switchable lipids can be used to control the opening and closing of ion channels that sense this pressure change. Having a molecular picture of the ion channels interacting with membranes that contain photo-switchable lipids would be a key step towards understanding how ion channels respond to lateral pressure, and could inform the design of new photo-switchable lipids tailored to specific ion channels.

Opioids are drug molecules that bind to membrane-embedded receptors called G Protein Coupled Receptors, GPCRs. Though effective in treating pain, opioids have the important disadvantage that they can be highly addictive. This caveat could be resolved by using opioid drug molecules that only bind to GPCRs in inflamed tissue at low pH. In the HLRN project we use quantum mechanical computations to characterize the electronic structure of opioid drug molecules, and classical mechanics to explore the response of GPCRs to the binding of opioids. One of the opioid molecules we study can change protonation, and we aim to describe it protonation-coupled binding to the receptor. We anticipate that the results of this work will inform on inter-molecular interactions that govern drug binding at physiological and low pH.

Figure 1: Photo-switchable lipids in trans vs. cis isomeric states. Bulk lipids molecules are colored according to the charge of the atoms, ranging from red – positively charged, to violet – negatively charged. Photo-switchable lipids are colored according to the atom type: carbon - cyan, nitrogen - blue, oxygen – red, and hydrogen – white. Water molecules are represented as semitransparent spheres.

Figure 2: μ-opioid receptor embedded in a lipid bilayer membrane (sticks coloured according to element: carbon - orange, nitrogen - blue, oxygen – red, hydrogen – not shown). The transmembrane part of the receptor is presented in blue, while the intracellular G-protein part is shown in yellow.