Title:	Investigation of dynamic conformational change and mechanism in the MAPEG enzymatic family
DNr:	SNIC 2015/1-87
Project Type:	SNIC Medium Compute
Principal Investigator:	Agnes Rinaldo-Matthis <Agnes.Rinaldo-Matthis@ki.se>
Affiliation:	Karolinska Institutet
Duration:	2015-03-01 – 2016-03-01
Classification:	10601
Homepage:	http://ki.se/ki/jsp/polopoly.jsp?d=31870&l=en
Keywords:

Abstract

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 as pharmaceuticals 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. For these reasons we would like to continue to complement our research with Molecular Dynamics simulations of these molecules in their physiological environment using the computational resources of SNIC. Results from such simulations using a SNAC Medium, 2014 allocation (snic2014-1-55) has provided considerable insight into the conformational dynamics of the protein mPGES-1 and provided insight into its chemical mechanism. This data is supported and complemented by a high resolution crystal structure of the enzyme and biochemical data from our lab, and these results will be the focus of a manuscript that will be submitted in the coming month. A medium allocation of 20 000 core hours per month would facilitate our continued investigation of these enzymes under simulation conditions that are physiologically accurate.