Authors Taekyung Kwon, Thaddeus Bargiello, Benoît Roux, Jeff Klauda, Andrew Harris, and Sunhwan Jo discuss the science behind the cover image of the latest issue of Biophysical Journal.
The cover image shows the structure of the open Cx26 hemichannel from the extracellular entrance following refinement of the crystal structure by all atom molecular dynamics simulation in an explicit membrane (ochre sticks). Hemichannels are a critical component of gap junctions, which are specialized molecular structures directly connecting the cytoplasm of two living cells.
The figure highlights the position of extensive van der Waals (limecolored spheres) and electrostatic networks (yellow sticks) that stabilize a portion of the pore lining region, the parahelix (red ribbons). This region of the channel poreundergoes a large conformational change to form a constriction that closes the channel in response to negative potentials by a process termed loop- or slow-gating. A significant feature, which is summarized in the image, is that the van der Waals network stabilizes the parahelix in each of the six individual subunits (ice blue ribbons) by interactions that are predominately restricted to individual subunits, whereas the interactions among charged residues extend across subunit boundaries to link the dynamic motions of the six component subunits. The electrostatic network likely contributes to the formation of the loop-gate voltage sensor; the extensive intersubunit interactions suggest that the loop-gating process occurs by a concerted mechanism. The interactions between these networks play an important role in mediating dynamic fluctuations observed in the open state in molecular dynamics simulations.
The long term objectives of our studies are to elucidate the molecular mechanism of voltage-dependent gating by defining the transition pathway that links open and closed states and how the two states are coupled by voltage. This goal requires knowledge of the structure and interactions that stabilize the two conformational endpoints, their conformational space and dynamics. Our current studies are focused on defining the closed state by experimental methods and to use this information to create and validate atomic models of the closed state. That the cover image closely corresponds to the Cx26 open channel is supported by our previous studies that demonstrated the close correspondence of I-V relations computed with grand canonical Monte Carlo Brownian dynamics to those determined experimentally (http://www.youtube.com/JGenPhysiol).
The image was created by Taekyung Kwon, the paper’s first author, using VMD software. We were very pleased that the image was chosen to appear on the cover and hope that it will increase the interest and exposure of our study to the readers of the Biophysical Journal. Our feeling is that atomic models of protein structures are inherently artistic and we were all impressed by the composition and quality of the image that Taekyung created. The image provides a succinct representation of the essential features of the Cx26 structure that were explored in the paper.
The atomic coordinates of the Cx26 structure refined by molecular dynamics simulation are available upon request and will be available for download from the Bargiello website: http://neuroscience.aecom.yu.edu/faculty/primary_faculty_pages/bargiello.html. Websites describing the research of other authors of the paper are:
Benoît Roux: http://thallium.bsd.uchicago.edu/RouxLab/
Jeff Klauda: http://terpconnect.umd.edu/~jbklauda/index.html
Andrew Harris: http://njms2.umdnj.edu/njmsweb/pharm_faculty/Harris.htm