Proteins are long chains of molecules consisting of polymers assembled from a large number of amino acids like beads on a necklace. The sequence of the amino acids in the polymer backbone is the primary structure of any given protein. There are 20 normal amino acids. Typical polypeptide chains contain about 100 to 600 amino acid molecules and have a molecular weight of about 15,000 to 70,000. Since amino acids have hydrophilic, hydrophobic, and amphilic groups, in an aqueous environment they tend to fold to form a locally ordered, 3D structure, called the secondary structure, that is characterized by a low-energy configuration with the hydrophilic groups outside and the hydrophobic groups inside. In general, simple proteins have a natural a-helix configuration. Another natural secondary configuration is a P-sheet. These two secondary configurations (a-helix and P-sheet) are the building blocks that assemble to form the final tertiary structure, which is held together by extensive-secondary interactions, such as van der Waals bonding. The tertiary structure is the complete 3D structure of one indivisible protein unit (i.e., one single covalent species). Sometimes, several proteins are bound together to form supramolecular aggregates that make up a quarternary structure. The quarternary structure, which is the highest level of structure, is formed by the noncovalent association of independent tertiary structure units.
Knowing the 3D structure of proteins is essential in understanding their function. The sequence (primary structure) provides little information about the function of proteins. To carry out their function, proteins must take on a particular shape, often referred to as an active form, through the folding process. Figure 2 shows an example of the 3D structure of bovine serum albumin (BSA). Folded proteins, such as egg albumin, can be unfolded by heating. Following heating, the albumin, which has undergone an irreversible folding conformation change, turns white. In this form albumin is said to be denatured. Denatured albumin cannot be reversed into its natural state. However, some
proteins can be denatured and renatured repeatedly; that is, they can be unfolded and refolded back to their natural configuration. Diseases such as Alzheimer's disease, cystic fibrosis, mad cow disease, an inherited form of emphysema, and even many cancers are believed to result from protein misfolding.
Extensive experimental and theoretical research efforts have been devoted to determine the structure of proteins. By using a combination of computational methods, mass spectroscopy, and nuclear magnetic resonance (NMR) techniques, researchers have identified an optimal set of small molecules for use in synthesizing novel bidentate antidotes or detection agents for clostridial neurotoxins, such as tetanus and botulinus. The crystal structure of the tetanus toxin C fragment (TetC, Protein Data Bank access code 1A8D) is shown with doxorubicin and a peptide computationally docked into sites 1 and 2, respectively, in Fig. 3. The structures of sialic acid and lavendustin A are shown about an NMR stack plot showing that lavendustin A binds to TetC (3).
The goal of understanding the structure and function of proteins as integrated processes in cells, often referred to as "system biology," presents a formidable challenge, much more difficult than that associated with determination of the human genome. Therefore, proteomics, which involves determination of the structure and function of proteins in cells, could be a research area that presents more challenges than genomics. Proteomics research directions can be categorized as structural and functional. Structural proteomics, or protein expression, measures the number and types of proteins present in normal and diseased cells. This approach is useful in defining the structure of proteins in a cell. However, the role of a protein in a disease is not defined simply by knowledge of its structure. An important function of proteins is in the transmission of signals through intricate protein pathways. Proteins interact with each other and with other organic molecules to form pathways. Functional proteomics involves the identification of protein interactions and signaling pathways within cells and their relationship to disease processes. Elucidating the role that proteins play in signaling pathways allows a better understanding of their function in cellular behavior and permits diagnosis of disease and, ultimately, identification of potential drug targets for preventive treatment. As described in the various chapters of this book, protein nanotechnology holds the promise of providing the critical tools needed to obtain real-time information about the signaling processes in cells.
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