A Systematic Approach Towards Elucidation Of The Mode Of Action Of A Bacterial Thermosensor

2511-Pos Board B281 Conformational Dynamics of Membrane-Bound a-Synuclein in a Highly Mobile Membrane Mimetic Joshua V. Vermaas, Emad Tajkhorshid. University of Illinois at Urbana-Champaign, Urbana, IL, USA. a-Synuclein is a widely studied unstructured protein that plays an important role in pathophysiology of Parkinson’s and Alzheimer’s diseases through its aggregation, a process closely connected to its binding to and restructuring of the cellular membrane. Thus the dynamics of the membrane-bound form of the protein is highly relevant to unravel the molecular mechanism of its involvement in these diseases. In order to characterize the dynamic range of conformations accessible to membrane-bound a-Synuclein, molecular dynamics offers a potentially powerful method, owing to its detailed atomistic and dynamic description of the semi-liquid environment of biological membranes. Nonetheless, the applicability of the method is hampered by the slow diffusion of lipid molecules when described atomisticly relative to simulation accessible timescales. We have developed and employed a novel membrane representation (termed HMMM, highly mobile membrane mimetic) with enhanced lipid dynamics and without compromising atomic details, which was used to perform 10 independent simulations of binding of a-Synuclein to bilayers composed of a mixture of PS and PC lipids. In all simulated systems, a-Synuclein spontaneously binds to the membrane without the application of an external force. Rather than converging to a single structure, these simulations capture an ensemble of diverse, highly dynamic structures of a-Synuclein in the presence of the membrane. While the observed conformational diversity can be attributed primarily to two highly flexible regions, namely near the turn and the region bracketed by critical Gly residues. Not only do the resulting ensemble of membrane-bound structures reflect the horseshoe-shape of the original structure, but also show similarities to a proposed linear configuration of the protein. The observed structural diversity suggests that in its membranebound form, a-Synuclein exists in an equilibrium between the horseshoe and linear conformations that have been also postulated experimentally.