title: A Molecular Dynamics Study of Allosteric Transitions in Leishmania mexicana Pyruvate Kinase.
abstract: A comparative molecular dynamics analysis of the pyruvate kinase from Leishmania mexicana is presented in the absence and presence of the allosteric effector fructose 2,6-bisphosphate. Comparisons of the simulations of the large 240 kDa apo and holo tetramers show that binding of fructose 2,6-bisphosphate cools the enzyme and reduces dynamic movement, particularly of the B-domain. The reduced dynamic movement of the holo form traps the pyruvate kinase tetramer in its enzymatically active state with the B-domain acting as a lid to cover the active site. The simulations are also consistent with a transition of the mobile active-site α6' helix, which would adopt a helical conformation in the active R-state and a less structured coil conformation in the inactive T-state. Analysis of the rigid body motions over the trajectory highlights the concerted anticorrelated rigid body rocking motion of the four protomers, which drives the T to R transition. The transitions predicted by these simulations are largely consistent with the Monod-Wyman-Changeux model for allosteric activation but also suggest that rigidification or cooling of the overall structure upon effector binding plays an additional role in enzyme activation.
authors.affiliation: The Centre for Translational and Chemical Biology, School of Biological Sciences, The University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Ankita
authors.initials: A
authors.lastname: Naithani
authors.affiliation: The Centre for Translational and Chemical Biology, School of Biological Sciences, The University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Paul
authors.initials: P
authors.lastname: Taylor
authors.affiliation: Department of Chemical and Biological Engineering, Koҫ University, Istanbul, Turkey. Electronic address: berman@ku.edu.tr.
authors.forename: Burak
authors.initials: B
authors.lastname: Erman
authors.affiliation: The Centre for Translational and Chemical Biology, School of Biological Sciences, The University of Edinburgh, Edinburgh, United Kingdom. Electronic address: m.walkinshaw@ed.ac.uk.
authors.forename: Malcolm D
authors.initials: MD
authors.lastname: Walkinshaw
mesh_terms: D000494:Allosteric Regulation; D005635:Fructosediphosphates / Q000378:metabolism; D007894:Leishmania mexicana; D056004:Molecular Dynamics Simulation; D009038:Motion; D055503:Protein Multimerization; D017433:Protein Structure, Secondary; D015800:Protozoan Proteins / Q000378:metabolism*; D011770:Pyruvate Kinase / Q000378:metabolism*
chemical_list: D005635:Fructosediphosphates; D015800:Protozoan Proteins; C027652:fructose 2,6-diphosphate; D011770:Pyruvate Kinase