In this chapter (and the following three chapters) we study mesoscopic mathematical models for the dynamics of engineered membranes. This chapter constructs mesoscopic models for the following two synthetic biological devices built out of artificial membranes:
The Chloride Intracellular Ion Channel (CLIC) family consists of six evolutionarily conserved proteins in humans. Members of this family are unusual, existing as both monomeric soluble proteins and as integral membrane proteins where they function as chloride selective ion channels, however no function has previously been assigned to their soluble form. Structural studies have shown that in the soluble form, CLIC proteins adopt a glutathione S-transferase (GST) fold, however, they have an active site with a conserved glutaredoxin monothiol motif, similar to the omega class GSTs. We demonstrate that CLIC proteins have glutaredoxin-like glutathione-dependent oxidoreductase enzymatic activity. CLICs 1, 2 and 4 demonstrate typical glutaredoxin-like activity using 2-hydroxyethyl disulfide as a substrate. Mutagenesis experiments identify cysteine 24 as the catalytic cysteine residue in CLIC1, which is consistent with its structure. CLIC1 was shown to reduce sodium selenite and dehydroascorbate in a glutathione-dependent manner. Previous electrophysiological studies have shown that the drugs IAA-94 and A9C specifically block CLIC channel activity. These same compounds inhibit CLIC1 oxidoreductase activity. This work for the first time assigns a functional activity to the soluble form of the CLIC proteins. Our results demonstrate that the soluble form of the CLIC proteins has an enzymatic activity that is distinct from the channel activity of their integral membrane form. This CLIC enzymatic activity may be important for protecting the intracellular environment against oxidation. It is also likely that this enzymatic activity regulates the CLIC ion channel function.
We now move on to a lower level of model abstraction compared to the continuum models of the previous chapters. This chapter describes how coarse-grained molecular dynamics (CGMD) can be used to study important properties of engineered artificial membranes (see Figure 14.1 for perspective on the levels of modeling abstraction). CGMD provides a dynamic simulation model of the engineered tethered membrane that is close to atomic resolution. As explained below, CGMD simulations can be used to estimate important parameters such as the diffusion coefficient of lipids and thereby facilitate building and designing membrane devices such as biosensors (discussed in Part II).
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