-----------------------------------------------------------------------
                                             BIOINFORMATICS COLLOQUIUM
						College of Science
                                              George Mason University
                       -----------------------------------------------------------------------

				   		       TBA
						 
                                               Sergei Sukharev, Ph.D.
				  
				               Department of Biology
                                            Biology-Psychology Building
                                              University of Maryland
                                           College Park, Maryland 20742


Abstract:
The mechanosensitive channel MscS is a ubiquitous osmolyte release valve that regulates 
turgor pressure in many walled cells. It is gated directly by tension transmitted through 
the surrounding lipid bilayer and shows an adaptive behavior involving opening followed 
by inactivation. The crystal structure of MscS solved by Rees and coworkers currently 
guides the quest for the details of its gating. Two major questions will be discussed: (1) 
what is the hydration state of the pore in the crystal conformation and (2) what type of 
protein motion may lead to the channel opening and inactivation.

MD simulations conducted with different water models suggest that in the crystal state 
the pore is completely dehydrated and thus non-conductive. This strongly implies that 
a critical wetting event must precede the onset of conduction, and that closure may be 
kinetically limited by a barrier associated with pore dewetting. We show experimental 
data illustrating these possibilities.

Molecular modeling of the opening transition has revealed straightening of the 
characteristic kink in the pore-lining TM3 helix near glycine 113. Repeated simulations 
of closing transitions indicated a high probability of alternative kink formation at 
glycine 121. We present experimental data showing that alternative kink formation 
distinguishes two non-conductive states of MscS, resting and inactivated. Based on the 
combined results of experiments and simulations, the mechanics of MscS will be discussed 
in the framework of its functional cycle.