In the centre of action: Unraveling conformational dynamics and catalytic protonation kinetics of enzyme active site residues

• Applicant: Dr. Ulrich Weininger
• Subject Area: Structural Biology ; Biochemistry ; Biophysics
• Term: from 2016 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 290128932

The goal of this research project is to study biologically relevant processes, as well as general and fundamental behaviours in proteins, at closest proximity to where they occur, in site- and time-resolved manner. Here we focus on aromatic side-chains, which play key roles in the packing of protein hydrophobic cores, binding interfaces and, in case of histidines and tyrosines, directly as catalytic residues in enzyme reactions. Despite their importance, their dynamics have not been studied in a comprehensive way due to methodological challenges. Here we apply methods developed by us to model proteins in order to understand the basic dynamic behaviours of aromatic side-chains, like ring-flips in tyrosines and phenylalanines, protonation reactions in tyrosines and histidines, and additionally tautomerizations in histidines. By this we are able to characterize such processes and deconvolute them from conformational changes. This allows us to address long-standing biochemical/biophysical questions regarding the dynamic functions and interactions of central human enzymes and get first hand insights beyond the structural level.

• DFG Programme: Research Grants