Project R-14993

Protein folding/non-folding and dynamics (PROFOUND) (Research)

Proteins are polymeric chains that underlie all functions in cells of all organisms. One of the most fascinating aspects of proteins is that they exist in constant motion, essential to their function, their interaction with other molecular entities in cells, their ability to enter membranes and travel to subcellular compartments. Moreover, when proteins exit from the cell's protein production factories they resemble extended threads, but soon afterwards exploit their intrinsic ability to be dynamic and acquire defined tightly packaged three-dimensional shapes. The latter process is known as folding. In all cases, proteins that cannot properly move or fold and misfold or aggregate cause pathologies such as Alzheimer's disease or non-functional hormone receptors. If we could rationally manipulate protein dynamics, we could develop novel therapies. This massive biomedical and clinical potential remains largely untapped because the processes of protein dynamics are still poorly understood. A significant hurdle for this is that several state-of-the-art techniques need to be used to properly capture dynamics and data need to be analyzed with robust statistics and the help of advanced computing. These tools demand expensive infrastructure investment and specialized expertise. The aim of the research network PROFOUND is to solidify a platform for future scientific and biomedical discovery of protein dynamics and folding in Flanders and Belgium. PROFOUND aims to satisfy the following targets: (-) Establish this research network as the core Flemish and Belgian "go to" consolidator of research in protein dynamics and folding. (-) Connect existing modules and establish a robust national pipeline of four core methodological directions in the study of advanced protein dynamics in Flanders (Hydrogen Deuterium Exchange mass spectrometry, single molecule FRET). (-) Efficient production and characterization of protein dynamics and folding with low resolution complementary biophysical tools. (-) Development of novel bioinformatics tools for data retrieval, analysis, visualization and statistical testing. (-) Strengthen and expand the existing tools of the Flemish knowledgebase with establishing long-term collaborations to individual experts in the French-speaking community and abroad (HDX-MS; protein folding, aggregation and biophysical analysis, protein folding dynamics and disordered proteins, membrane-related chaperones and outer membrane folding, cross-linking methods). (-) Establish links to orthogonal studies with complementary tools that are currently unavailable in Flanders or available but not specializing in the interests of PROFOUND. These will be provided by outside global experts particularly in optical tweezers to study chaperones, protein folding and protein dynamics, NMR in protein folding and chaperone interactions and Molecular Dynamics simulations of protein motions. Important additional dimensions that will be detailed in this proposal include training of junior scientists, establishing mechanisms for easy access to the PROFOUND pipeline of other Flemish and Belgian scientists who are non-experts in the methodologies and dissemination activities that will include theoretical and hands-on workshops, WWW-based information and cloud-provided lecture series.

01 January 2021 - 31 December 2025