Globular protein mimics

Figure 28 A dendrimer-based approach for the design of globular protein mimic using glutamic (Glu) and aspartic (Asp) acids as the building blocks and adamantyl as the core [151].

Since dendrimers are often pursued as globular protein mimics, it is useful to be able to vary each monomer unit from the other, ie introduce sequences within dendrimers. For achieving such a possibility, the convergent approach is an ideal synthetic protocol. The Thayumanavan group has developed two synthetic protocols in which the peripheral functionalities of the dendrimers are all different from each other (21,22). In the first approach, we used an AB2 monomer unit in which one of the B units is protected. This approach was demonstrated by the monoprotection of one of the phenolic groups of 3,5-dihydroxybenzyl alcohol with an allyl moiety. The resultant monomer was treated with one alkylating agent to... 

Owing to their size and the feasibility of controlling the dendrimer structure and globular morphology via their synthesis, dendrimers with chiral branching scaffold are of interest as potential protein mimics. In addition, the introduction of chiral branching units or spacers into the molecular scaffold should lead to the development of non-symmetrical macromolecular conformations and provide chiral cavities for asymmetrical catalysis or chiral recognition processes. 

A typical structure of a water-soluble globular protein consists of hydrophilic amino acid residues outside and hydrophobic ones inside. The hydrophobic environments support various electrostatic interactions within the protein, which plays a crucial role in the enzymatic reaction. Therefore, a simple model complex involving such electrostatic interactions must have hydrophobic environments around the active site such that they are not much influenced by an external effect of solvent. It follows that the models must to some extent be examined in a nonpolar solvent in order to mimic the behavior of native ones. 

The problem of solubilization in complex mixed fluids still remains open. Model mixed systems include surfactant solutions in the presence of inorganic two-dimensional objects such as clay, surfactants in the presence of linear polymers, and surfactants in the presence of globular nanoparticles, either inorganic or globular proteins. All of these model systems may be used to mimic solubilization in the environment. A general approach to this open problem is dealt with by Klumpp and Schwuger (59), who demonstrated that surfactants and multivalent ions are competitors for exchange at the surface of clays (as they should also be on humic acids). Once the mixed system is formed, the solubilization power (MAC) of the mixed surfactant system may be widely enhanced by reference to the separated surfactant and colloid. A spectacular example has been described... 

Forced unfolding simulations have also been applied to globular proteins to determine whether the unfolding response mimics that observed for... 

Biological membranes typically contain about 50% each of lipids and proteins. Perhaps the most familiar model of the membrane make-up has been that of Singer and Nicolson (shown in Fig. 5.19). In it the lipids form a bilayer similar to those found in lamellar liquid crystals. The bilayer structure is spanned by large globular protein complexes which serve as selective barriers to the transportation of metabolites in and out of the cell. In addition to this they also confer a degree of stability on the structure, preventing it from breaking apart. The exact nature of this stabilization is obviously rather complex and extremely difficult to mimic in the synthesis of artificial membranes. Therefore, polymerization of the... 

The field of synthetic enzyme models encompasses attempts to prepare enzymelike functional macromolecules by chemical synthesis [30]. One particularly relevant approach to such enzyme mimics concerns dendrimers, which are treelike synthetic macromolecules with a globular shape similar to a folded protein, and useful in a range of applications including catalysis [31]. Peptide dendrimers, which, like proteins, are composed of amino acids, are particularly well suited as mimics for proteins and enzymes [32]. These dendrimers can be prepared using combinatorial chemistry methods on solid support [33], similar to those used in the context of catalyst and ligand discovery programs in chemistry [34]. Peptide dendrimers used multivalency effects at the dendrimer surface to trigger cooperativity between amino acids, as has been observed in various esterase enzyme models [35]. 

In 1991, Luger et al. revealed by X-ray analysis the crystal structure of a natural DNA-histone complex. The X-ray structure shows in atomic detail how the histone protein octamer is assembled and how the base pairs of DNA are organized into a superhelix around it [74]. Since then this protein structure with cationic amino acids on the surface has acted as a model for the rational design of dendritic polymer-based gene vectors to mimic the globular shape of the natural histone complex [75-77]. 

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