Bulletin of the American Physical Society
2009 APS March Meeting
Volume 54, Number 1
Monday–Friday, March 16–20, 2009; Pittsburgh, Pennsylvania
Session X38: Focus Session: Ion Channel Physics and Chemical Physics II |
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Sponsoring Units: DCP Chair: Thomas Beck, University of Cincinnati Room: 410 |
Thursday, March 19, 2009 2:30PM - 3:06PM |
X38.00001: Dynamics of Kv2.1 channel cluster formation in mammalian neurons. Invited Speaker: Kv2.1 are potassium channels that play an important role in multiple organs and tissues. In particular, in mammalian neurons Kv2.1 channels have an enormous neuroprotective function attained by their ability to form large clusters on the surface of the neuronal cell body. The regulation of Kv2.1 channel clusters is a key factor in protecting the brain, particularly under sudden ischemic conditions such as those encountered in stroke. It is speculated that this kind of stimulus induces channel declustering in order to suppress neuronal hyperexcitability (i.e. seizures). However, the physical mechanism that forms and maintains Kv2.1 clusters has remained largely unknown. We are investigating the dynamics of channel clusters at the single molecule level using particle tracking with nanometer accuracy in live cells. Here, the cluster structure and individual channels are imaged simultaneously in a total internal reflection microscope. While most Kv2.1 channels in the cell are labeled with green fluorescent proteins (GFP), only a few individual channels are tagged with red quantum dots. This approach allows us to track single molecules and probe their interaction with the cluster perimeter. Different models for the molecular mechanism that localizes Kv2.1 clusters on the cell surface and the implications of our data will be discussed. [Preview Abstract] |
Thursday, March 19, 2009 3:06PM - 3:42PM |
X38.00002: Surfaces and boundaries in the mechanosensitive channel gating Invited Speaker: Mechanosensitive (MS) channels are gated by tension transmitted through the surrounding lipid bilayer. Inorganic ions or amphipathic modifiers that interact with the bilayer surface alter the packing of lipids and perturb the lateral pressure. We describe the effects of lanthanide ions, fluorinated alcohols and esters of parabenzoic acid as potent modifiers of MS channel gating. The other boundary that plays a critical role in channel gating is the water-vapor interface resulting from capillary dewetting of the hydrophobic gate. Molecular simulations predict two alternate positions for this boundary in the pore of the mechanosensitive channel MscS. We approached this problem experimentally by hydrophilizing the outer segment of the pore to resolve if it is `dry' in the closed state. We observed a reduction in activating tension, substantial changes in MscS kinetics and complete removal of gating hysteresis. The kinetic treatment of channel traces recorded in response to steps of tension suggested the sequence of events that leads to the channel opening implying that pore hydration and dewetting are the rate-limiting steps in MscS transitions. [Preview Abstract] |
Thursday, March 19, 2009 3:42PM - 4:18PM |
X38.00003: Modeling Conformational Transitions and Energetics of Ligand Binding with the Glutamate Receptor Ligand Binding Domain Invited Speaker: Understanding of protein motion and energetics of conformational transitions is crucial to understanding protein function. The glutamate receptor ligand binding domain (GluR2 S1S2) is a two lobe protein, which binds ligand at the interface of two lobes and undergoes conformational transition. The cleft closure conformational transition of S1S2 has been implicated in gating of the ion channel formed by the transmembrane domain of the receptor. In this study we present a composite multi-faceted theoretical analysis of the detailed mechanism of this conformational transition based on rigid cluster decomposition of the protein structure [1] and identifying hydrogen bonds that are responsible for stabilizing the closed conformation [2]. Free energy of the protein reorganization upon ligand binding was calculated using combined Thermodynamic Integration (TI) and Umbrella Sampling (US) simulations [3]. Ligand -- protein interactions in the binding cleft were analyzed using Molecular Dynamics, continuum electrostatics and QM/MM models [4]. All model calculations compare well with corresponding experimental measurements. \\[4pt] [1] Protein Flexibility using Constraints from Molecular Dynamics Simulations \textit{T. Mamonova, B. Hespenheide, R. Straub, M. F. Thorpe, M. G. Kurnikova} , Phys. Biol., 2, S137 (2005)\\[0pt] [2] Theoretical Study of the Glutamate Receptor Ligand Binding Domain Flexibility and Conformational Reorganization \textit{T. Mamonova, K. Speranskiy, and M. Kurnikova }, Prot.: Struct., Func., Bioinf., 73,656 (2008)\\[0pt] [3] Energetics of the cleft closing transition and glutamate binding in the Glutamate Receptor ligand Binding Domain~\textit{T. Mamonova, M. Yonkunas, and M. Kurnikova~ }Biochemistry~$47$, 11077 (2008)\\[0pt] [4] On the Binding Determinants of the Glutamate Agonist with the Glutamate Receptor Ligand Binding Domain \textit{K. Speranskiy and M. Kurnikova} Biochemistry 44, 11208 (2005) [Preview Abstract] |
Thursday, March 19, 2009 4:18PM - 4:30PM |
X38.00004: ABSTRACT WITHDRAWN |
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