Hierarchical protein design

The first requirement for threading is to have a database of all the known different protein folds. Eisenberg has used his own library of about 800 folds, which represents a minimally redundant set of the more than 6000 structures deposited at the Protein Data Bank. Other groups use databases available on the World Wide Web, where the folds are hierarchically ordered according to structural and functional similarities, such as SCOP, designed by Alexey Murzin and Cyrus Chothia in Cambridge, UK. 

Hierarchic design of assembled structures should be important for preparation of functional mesoscopic structures. Typical examples can be seen in biological systems where tissues of organisms in living systems consist of assemblies of cells with cell membranes composed of self-assembled lipids, proteins, saccharides, etc. Therefore, tissues and organisms can be regarded as (at least) two-level assemblies lipid to... 

Biological macromolecules such as DNA and proteins are typical polyelectrolytes, which further hierarchically self-assemble into complicated supramolecular structures such as coiled coil (helix bundle) superstructures, which are responsible for their sophisticated functions [152,153]. Therefore, with implications for biological superstructures and functions, the design and synthesis of supramolecular helical assemblies with a controlled helicity have attracted great interest. 

Most of the studies based on virtual screeiung use a hierarchical approach combiiung several conceptually different techniques. The most common combination used is a 3D pharmacophore modeling followed by a docking study, hi Figure 15.58 is reported an illustrative example of this combined use a set of 10 known inhibitors of Human Rhinovirus Coat protein was used to design a 3D pharmacophore... 

The wealth of natural examples provides immense inspiration for the molecular design of novel peptide-based materials that can be potentially applied as devices, sensors, and biomaterials for medical applications. In addition to hierarchical self-assembly, nature uses other mechanisms, for example, enzyme-mediated covalent cross-linking, to build up structural proteins and higher-ordered structures. In the following sections we will focus on manmade peptide-based materials that belong to the three classes listed below. They will be split with respect to the underlying design concept into materials formed by ... 

We can also mention the use of bio-sourced building blocks based on cellulose or dextran. Kadla et al. described value-added materials from naturally abundant polymers for system that may serve as a platform for the design and development of biosensors [197]. A hierarchically strucmred honeycomb film from dextran-ft-PS amphiphilic linear diblock copolymers has also been described by Chen et al. leading to ordered porous bio-hybrid films. [198] Honeycomb patterned surfaces functionalized with biomolecules for specific recognition of proteins or bacteria have been also achieved either by self-assembly of amphiphilic copolymers based on galactose moieties [155] or by post-modification with peptide sequences [199]. 

Figure 38 Examples of hierarchical self-assembly in (a) biological and (b) synthetic systems. The buildup of structural complexity is programmed into the protein sequence or the functional polymer design.

The more complicated design of tertiary and quaternary stmcture in proteins has been attained in some cases. However, the ability to form hierarchically ordered stmctures, or self-assemble folded stmctural units into well-defined higher order assemblies, from any non-natural backbone remains an important unsolved problem. A few preliminary reports, including work on p-peptides and peptoids, with stmcture beyond the helix were reported recently [20-22]. These two backbones represent the more weU studied sequences of foldamers and so initial reports toward stmctures beyond secondary elements can be expected. However, given more than a decade of foldamer research, little work toward these higher order stmctures has been reported. 

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