Investigation of dynamic conformational change and mechanism in the MAPEG enzymatic family
Title: Investigation of dynamic conformational change and mechanism in the MAPEG enzymatic family
SNIC Project: SNIC 2014/1-55
Project Type: SNAC Medium
Principal Investigator: Agnes Rinaldo-Matthis <>
Affiliation: Karolinska Institutet
Duration: 2014-03-01 – 2015-03-01
Classification: 10601


Our research focuses on the chemistry of the MAPEG (Membrane-Associated Proteins in Eicosanoid and Glutathione metabolism) enzymatic family. Eicosanoids play an intimate role in the affection of the bodies immune response via their mediation of acute inflammation, fever and clinical conditions such as thrombosis, cancer, atherosclerosis, asthma and rhinitis. Several compounds that modulate their biosynthesis and mode of action are currently available and widely used. Understanding the chemistry of the MAPEG enzymes is of particular importance within such a clinical context, since they are known to be responsible for the downstream differentiation of eicosanoids to specific chemical messengers, such as leukotrienes and prostaglandins. For example, one member of this enzymatic family that we currently study is dynamically up-regulated by the immune system to synthesise prostaglandin E2, the principle effector of localised pain, swelling and fever under these conditions. Gaining a more fundamental chemical understanding of terminal enzymes in eicosanoid biochemical pathways such as this may be indispensable for finely modulating the bodies immune response without inducing harmful side effects. One of the most powerful techniques in understanding the chemical mechanism of enzymes is X-ray crystallography, and our research group has contributed considerable insight into this enzymatic family's structure and function using this method. The method is limited however, in its necessity for a selection from many dynamic conformational states via the crystallisation process. In addition, the conditions of crystallisation are often very different from the physiological environment of the enzyme being studied. The effect of removing enzymes such as those of the MAPEG family from a biological membrane for instance, is often very hard to quantify. For these reasons we would like to complement our research with Molecular Dynamics simulations of these molecules in their physiological environment using the computational resources of SNIC. Preliminary results from a molecular dynamics simulations using a common small allocation project of the Karolinska Institutet Protein Science Facility provided promising and insightful results, however, we have quickly exceeded our qouta and wish to do additional experiments for publication. A medium allocation of 100 000 node hours per month would facilitate our further investigation of these enzymes under physiologically accurate conditions.