Enzymes are remarkable catalysts that can provide rate enhancements of many orders of magnitude compared to the uncatalyzed reaction. The fundamental understanding of the origin of enzymatic catalytic acceleration is still lacking and intensely debated. Currently, at least four explanations of catalytic power co-exists; i) Pauling’s suggestion of transition-state (TS) stabilization, ii) Jencks proposal of entropic factors as the main driving force, iii) the effect of having correlated motions of domains and iv) proposals concerning the Michaelis complex where the ability of the enzyme to accommodate Near Attack Conformers (NACs) of the substrate is pointed out. These explanations of enzymatic power all concerns the dynamics of the E·S complex as well as the binding of the substrate and/or the TS in the active site of the enzyme. A considerable part of the research in the group concerns computational studies of these issues.
- Pyruvate Decarboxylase: We have carried out extensive MD simulations of pyruvate decarboxylase. From the analysis we suggested that ThDP is activated from an imino-tautomer to form the catalytic ylide-form. The simulations also gave rise to a revised binding geometry of pyruvate where a hydrogen bond to Tyr290 is preferred over the previously proposed hydrogen bond to the exocyclic amine group. From a NAC analysis, we proposed a modified reaction pathway for the initial nucleophilic attack of the overall reaction mechanism. Based on the findings from the MD-study, we have done DFT calculations focusing on identifying the transition states of the individual reactions steps as well as computing the related reaction barriers. Future projects will study this proposed pathway with QM/MM methods.
- Membrane Embedded Enzymes: We have recently become involved in studying the dynamical properties of various P-type ATPases (pumps). We study the proposed catalytic/pumping cycle of the calcium pump, SERCA, as structural information is available for this system in all proposed intermediate states. Other studies focus on understanding the dynamic and catalytic functioning of the GlpG rhomboid protease detailing possible pathways for substrate entrance and catalytic reaction.