Molecular Dynamics Simulations of Outer Membrane Phospholipase A
Topic Categories:  8E Molecular Dynamics ;  1H Membrane Proteins
Marc Baaden1, Christoph Meier2, Mark S. P. Sansom3.
1IBPC, CNRS UPR9080, Paris, France, 2The Wellcome Trust Centre for Human Genetics, Oxford, United Kingdom, 3Laboratory of Molecular Biophysics, University of Oxford, United Kingdom.

Presentation Number: 1961-Pos
Poster Board Number: B58
Outer Membrane Phospholipase A protein (OMPLA) is found in the outer membranes of many Gram-negative bacteria where it hydrolyses phospholipids and is involved in a variety of cellular functions, including bacterial virulence and toxin secretion. The protein exists in monomeric and dimeric form and its activation requires calcium-induced dimerisation plus bilayer perturbation. We present results of molecular dynamics (MD) simulations in a fully solvated phospholipid (POPC) bilayer to probe the conformational dynamics of calcium-free monomeric OMPLA, of the Ca(2+)-bound dimer, and of the Ca(2+)-bound dimer with a substrate analogue covalently linked to the active site serine. All simulations were stable, but revealed significant differences in the flexibility of the active site and the hydrophobic substrate binding cleft. The dimer is considerably less flexible than the monomer, especially around the active site. A model is proposed whereby this increased stability of the active site in the dimer is a consequence of the local ordering of water around the nearby calcium ion. In the absence of bound substrate analogue, the hydrophobic substrate-binding cleft of dimeric OMPLA collapses, which restricts the active site accessibility. The observed differences in conformational dynamics may be related to enzyme activation.