Datorbaserade studier av biologisk katalys och molekylär igenkänning
Tidsperiod: 2015-01-01 till 2018-12-31
Projektledare: Johan Åqvist
Budget: 3 200 000 SEK
This project deals with computational studies in the general areas of biological catalysis and molecular recognition. We emphasize what may be called quantitative computational structural biology, where the goal is to deliver accurate descriptions of energetics and kinetics, directly from 3D structural information, for biochemical systems of key importance. We will specifically focus on three fields where we have made considerable progress in recent years. These are (i) mechanisms and accuracy of protein synthesis on the ribosome, (ii) adaptation of enzymes to cold environments and evolutionary optimization of thermodynamic activation parameters in enzyme catalysis and (iii) development of computational techniques for structure-based ligand design. The overall goal in first area is to provide a quantitative structure-based energetic description of the key steps in protein synthesis and explore new targets for its inhibition. In the second area our aim is to explain the structural and energetic principles of enzyme cold-adaptation and answer longstanding questions regarding entropic and enthalpic contributions to enzyme catalysis. Finally, we will follow several promising new routes for further advancing computational structure-based ligand design methodology. Here, techniques for quantitative analysis and prediction of receptor-ligand binding affinities and their thermodynamic components, are of particular interest in structure-based drug discovery.