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Protein signalling pathways elucidated via novel correlation analysis of molecular dynamics simulations

Final Report Summary - PROTSIGN (Protein signalling pathways elucidated via novel correlation analysis of molecular dynamics simulations)

Signal transduction enables a biological system to respond to an external stimulus such as incoming light, sound, or odour. Living cells most frequently respond to chemical stimuli transmitted by the binding of signalling molecules such as hormones, neurotransmitters, or growth factors. Such chemical signals are typically recognised by a membrane receptor which triggers a cascade of signalling events in the cell interior, leading to, for instance, activation of a gene, chemotaxis, or cell proliferation. Dysfunction of signalling cascades is related to a number a severe disorders such as cancer, Alzheimer's disease, heart disease, or autoimmunity.

Signal transduction occurs over different scales, down to the transmission of information within an individual protein. The latter is frequently referred to as 'protein allostery', a phenomenon that has been detected for e.g. hemoglobin, but which is still not understood on a molecular level. In allosteric proteins, it is clear that correlations between distant sites, for instance between a binding site for a ligand and an active site, are encoded in the protein matrix. But how? To address that question, we aimed to employ molecular dynamics (MD) simulations. That technique is in theory able to sample the structural flexibility of proteins and to detect such correlations and hence we could simulate spontaneous allosteric transitions of hemoglobin. Through multiple such transitions, we could measure correlations between distant sites and quantify allosteric effects. In cooperation with the Richard Neutze lab (Gothenburg), we applied MD simulations to rationalise structural kinetics of proteorhodopsin, a homologue to the GPCR family of signalling proteins.

However, we also noticed that the detection of long-range correlations in allosteric proteins is in many cases more challenging than previously expected, mainly because the sampling of relevant conformational transitions is still not possible with present computing power. Therefore, we decided to postpone parts of our efforts until the required resources are available. Besides the published studies on signalling in hemoglobin and proteorhodopsin, we focused on two alternative projects to support the prospects of the Marie-Curie fellow to become an independent researcher.

On the one hand, we employed MD simulations to study the chemistry of aerosols, whose properties are the cause of a large part of the uncertainty in climate research. We focused on seawater that becomes airborne in the form of droplets. Ions travelling with the water droplets play an important role in the chemistry of the atmosphere. First simulations and later experiments showed that, surprisingly, several ions prefer to be located at the water surface, with implications on processes such as the ozone cycle. However, why halide ions are located on the surface has been under debate. We could resolve the driving forces underlying that behaviour and published the results in Proc. Natl. Acad. Sci. U.S.A. We derived the complete thermodynamics of ion solvation at the water surface, disproving simplified mechanistic or structural explanations, and, enhances the understanding of aerosols.

On the other hand, we used MD simulations to improve the quantitative understanding of solute permeation across biological membranes, which is highly relevant from biophysical, physiological, and pharmacological perspectives. Our simulations derived the detailed energetics of such solute permeation across biological lipid membranes leading to a number of publications in excellent journals.

Based on the scientific results achieved during this Marie-Curie fellowship, the fellow has now received a highly competitive 5-year grant to build up a junior research group, funded by the Emmy-Noether programme of the German Research Foundation ('DFG'). The Marie-Curie fellowship has contributed substantially to the fellow's development to become an independent researcher.
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