Lay summary
Multiscale Modelling of Electronically Triggered Biological Signaling

The ways nature ensures the passage of biological information through a complex network of specially designed signaling routes is of pivotal importance for the survival and fitness of an organism. Through the activation of signaling cascades, it can respond to external and internal stimuli and thus quickly adapt to changes in the environment. These stimuli can be as diverse as changes in temperature, mechanical stress, light absorption, or the interaction with electric fields or different kinds of molecules. The stimuli lead to the activation of specific transmembrane receptors or cytoplasmic ligand-activated transcription activators. All of them share the common feature that localized electronic or structural changes are able to trigger larger conformational transformations that set off a cascade of biochemical events carried out by different cellular components and linked through second messengers by which the original signal can be transduced, relayed and amplified. A prototypical example is the light sensitive visual pigment rhodopsin for which a single photon can initiate cis-trans photoisomerization of the retinal chromophore that triggers a conformational change of the protein which leads to activation of up to 2000 effector molecules per second. Disturbances of the signaling pathways are key for a wide range of pathologies such as cancer, diabetes, cardiac failure, neurodegenerative diseases, immunodeficiences, inflammatory and autoimmune diseases and aging. Not surprisingly, a majority of the available drugs today is targeted to molecular receptors. The understanding of biological signaling pathways is therefore of primordial importance both from a fundamental and practical points of view. Although the amount of available experimental data on molecular receptors and their associated signaling pathways is constantly increasing, the underlying molecular mechanisms are often not known.
These events span many different orders of length and time scales, from the electronic/atomic level to the mesoscopic/microscopic domain with accompanying time windows that range from femtoseconds to milliseconds and seconds typical for the full activation of a cascade. A theoretical modeling is thus challenging and necessitates a truly multiscale approach where methods of different fields (quantum mechanical electronic structure calculations, atomistic classical molecular dynamics simulations, coarse grain models and system biology approaches) have to be combined ultimately.
In this proposal, we want to concentrate in a first step on the early signaling events that encompass characteristic length scales from the electronic level to systems of few tens to hundreds thousands of atoms in the femtoseconds to microsecond time range. In particular, we want to focus on electronically driven signaling to follow the transduction of the biological signal from its creation on the electronic level to the large scale conformational changes that are induced in consequence.