Biophysics Seminar

Description

Title: Molecular Navigation Through Connexin Channels: First Steps

Speaker: Andrew Harris, Rutgers University

Notes: http://marylandbiophysics.umd.edu/seminars/

Abstract:

Connexin proteins form wide pores in plasma membrane and between adjacent cells. These gated pores are permeable to atomic ions and small molecules, thereby mediating electrical and molecular signaling. The intercellular channels (“gap junction channels”) permit cytosolic molecules such as IP3 and cAMP to pass between cells. The plasma membrane channels (“hemichannels”) play autocrine/paracrine roles by releasing molecules such as glutamate and ATP into the extracellular environment. The molecular signaling mediated by connexin channels is of critical biomedical importance, being intimately involved in development, normal physiology, and response to trauma and disease. Defects in connexin channels cause human pathologies.

Although connexin channels as a class are permeable to a wide variety of small molecules, channels formed by each of the 21 human connexin isoforms have strikingly different ionic and molecular selectivities. The molecular permselectivity is not a simple function of pore width but depends on as yet uncharacterized interactions between specific permeants and the pore lumen of each connexin isoform; there is little correlation among channel unitary conductance, limiting pore diameter and/or charge selectivity.

To help elucidate the mechanisms that influence and define selective molecular permeation, molecular dynamics simulations were applied to similar two molecules – one permeant and one not – in a connexin hemichannel.

The results highlight issues and factors that come into play in selective molecular permeation of wide pores that are different from those that dominate permeation of atomic ions through ion-selective pores. These include mechanisms of selectivity involving low-energy interactions, and ‘‘permeant’’ and side-chain flexibility, orientation and anisotropy. A key element of the energetic landscape is the entropic contribution due to molecules that can occupy many configurations and orientations in a non-rigid water-filled pore. Pore width influences the energetic landscapes experienced by these molecules and differences between them, but other factors are strongly involved. Also, for both the permeant and impermeant test molecules, the computed energetic barriers extend through most of the pore, without significant binding (energy wells).

The results suggest that this type of analysis may be useful in exploring the molecular basis by which connexin channels distinguish among (potential) permeating molecules, and how mutations may alter the permeation process.

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