Rob D Coalson

Theoretical/Computational Studies of Structure/Function Relations in Nanopores:

The Nuclear Pore Complex. 

The Nuclear Pore Complex (NPC) perforates the nuclear membrane and allows the flow of large biomolecules between the nucleoplasm and the cytoplasm in eukaryotic cells.  It is the largest protein complex in the cell.  Its detailed structure has not yet been fully elucidated, but it is known that the pore region is lined with natively unfolded nucleoporin proteins. These proteins extend into the center of the pore in a polymer brush configuration. They form a tight barrier to the passage of large biomolecules.  The amino acid sequence of the natively unfolded nucleoporins includes hydrophobic repeat segments.  These hydrophobic segments bind transiently to hydrophobic grooves on the outside of special globular receptor proteins (Nuclear Transport Factors [NTFs]), which also bind biomolecules (“cargoes”) waiting to be transported into/out of the nucleus.  Transient binding of the nucleoporin (nup) strands to the receptor protein NTFs allows the NTFs (with cargo attached) to transport through the NPC in a selective and efficient way.  The exact mechanism of the transport process is not known.  We use coarse-grained models to investigate basic physico-chemical models of NPC function.  These include bead-spring models of the nup chains that are grafted to the inside of the NPC pore and interact with spherical NTFs.  Coarse-grained MD simulations of these systems yield insight into the way the receptor proteins interact with the nup filiaments, such as inducing morphology changes in the nup brush and diffusing through the brush barrier from one side of the NPC to the other.  In addition, coarse-grained statistical mechanical models including Flory-Huggins and Self-Consistent Field Theories are utilized to assess trends in relevant equilibrium aspects of NPC function.

Smart Nanoparticle/Polymer Brush Composites. 

The biological NPC inspires design of synthetic polymer brush systems in which the brush morphology is modified upon binding of nanoparticles that attract to brush monomers.  In the context of an inside-grafted cylindrical brush (directly analogous to the NPC), binding of attractive nanoparticles to the polymer strands causes partial compression of the polymer brush (retraction toward the binding surface).  This opens up space along the center of the channel.  Analyte molecules small enough to fit through the opening can diffuse through the pore.  The flow of larger analyte molecules is blocked.  The degree of retraction of the brush can be precisely controlled by the concentration of nanoparticles in solution.   In this way, a size-selective molecular sieve can be generated, with an easily controllable aperture size.  We seek next to incorporate chemical features of the analyte molecules, in addition to their geometric size, into the sieving process.

Biological Ion Channels. 

These are proteins that span cytoplasmic membranes (e.g., the outer cell membrane).  They are responsible for the selective passage of ions from one side of the membrane to the other.  Structural details of many ion channels are available from X-ray and cryo-electron microscopy experiments.  We are interested in studying the gating and ion permeation properties of specific channels based on specific structural data, using large-scale MD simulations as well as coarse-grained electrostatic methods (e.g., Poisson-Nernst-Planck theory) and discrete state kinetic models.  In addition, we seek to understand general, universal properties of ion permeation that are shared by all ion channels, regardless of their structural details.  For example: statistics of ion permeation events, which are constrained by non-equilibrium fluctuation theorems.

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Dr. Coalson's complete publication list can be found here . Clickable links to recent publications are provided below.