Protein structures, compact

Proteins derive their powerful and diverse capacity for molecular recognition and catalysis from their ability to fold into defined secondary and tertiary structures and display specific functional groups at precise locations in space. Functional protein domains are typically 50-200 residues in length and utilize a specific sequence of side chains to encode folded structures that have a compact hydrophobic core and a hydrophilic surface. Mimicry of protein structure and function by non-natural ohgomers such as peptoids wiU not only require the synthesis of >50mers with a variety of side chains, but wiU also require these non-natural sequences to adopt, in water, tertiary structures that are rich in secondary structure. 

Globular proteins are compact, are roughly spherical or ovoid in shape, and have axial ratios (the ratio of their shortest to longest dimensions) of not over 3. Most enzymes are globular proteins, whose large internal volume provides ample space in which to construct cavities of the specific shape, charge, and hy-drophobicity or hydrophilicity required to bind substrates and promote catalysis. By contrast, many structural proteins adopt highly extended conformations. These fibrous proteins possess axial ratios of 10 or more. 

A particular goal of chemical theory is to predict protein structure from the amino acid sequence—to calculate how polypeptides fold into the compact geometries of proteins. One strategy is to develop methods (often based on bioinformatics) for predicting structures approximately and then refining the structures... 

Myelin in situ has a water content of about 40%. The dry mass of both CNS and PNS myelin is characterized by a high proportion of lipid (70-85%) and, consequently, a low proportion of protein (15-30%). By comparison, most biological membranes have a higher ratio of proteins to lipids. The currently accepted view of membrane structure is that of a lipid bilayer with integral membrane proteins embedded in the bilayer and other extrinsic proteins attached to one surface or the other by weaker linkages. Proteins and lipids are asymmetrically distributed in this bilayer, with only partial asymmetry of the lipids. The proposed molecular architecture of the layered membranes of compact myelin fits such a concept (Fig. 4-11). Models of compact myelin are based on data from electron microscopy, immunostaining, X-ray diffraction, surface probes studies, structural abnormalities in mutant mice, correlations between structure and composition in various species, and predictions of protein structure from sequencing information [4]. 

Myelin components exhibit great heterogeneity of metabolic turnover. One of the novel characteristics of myelin demonstrated in early biochemical studies was that its overall rate of metabolic turnover is substantially slower than that of other neural membranes [1]. A standard type of experiment was to evaluate lipid or protein turnover by injecting rat brains with a radioactive metabolic precursor and then follow loss of radioactivity from individual components as a function of time. Structural lipid components of myelin, notably cholesterol, cerebro-side and sulfatide, as well as proteins of compact myelin, are relatively stable, with half-lives of the order of many months. One complication in interpreting these studies is that the metabolic turnover of individual myelin components is multiphasic - consisting of an initial rapid loss of radioactivity followed by a much longer slower loss. 

Protein domains are the common currency of protein structure and function. Protein domains are discrete structural units that fold up to form a compact globular shape. Experiments on protein structure and function have been greatly aided by consideration of the modular nature of proteins. This has allowed very large proteins to be studied. The expression of individual domains has allowed the intractable giant muscle protein titin to be structurally studied (Pfuhl and Pastore, 1995). Protein domains can be found in a variety of contexts, (Fig. 1), in association with a range of unrelated domains and in a variety of orders. Ultimately protein domains are defined at the level of three-dimensional structure however, many protein domains have been described at the level of sequence. The success of sequence-based methods has been demonstrated by numerous confirmations, by elucidation of the three-dimensional structure of the domain. 

Inspection of protein structures can show which regions of a protein form compact globular structure and hence the domains of the protein. Several methods can be used to automatically extract domain definitions from three-dimensional structures (Holm and Sander, 1995 Islam et al.,... 

The use of sequence information to frame structural, functional, and evolutionary hypotheses represents a major challenge for the postgeno-mic era. Central to an understanding of the evolution of sequence families is the concept of the domain a structurally conserved, genetically mobile unit. When viewed at the three-dimensional level of protein structure, a domain is a compact arrangement of secondary structures connected by linker polypeptides. It usually folds independently and possesses a relatively hydrophobic core (Janin and Chothia, 1985). The importance of domains is that they cannot be divided into smaller units— they represent a fundamental building block that can be used to understand the evolution of proteins. 

Protein chains are not the sprawling, ill-defined structures that might be expected from a single polypeptide chain. Most proteins are compact molecules, and the relative positions of atoms in the molecule contribute significantly to its biological role. A particularly important contributor to the shape of proteins is provided by the peptide bond itself. Drawn in its simplest form, one might expect free rotation about single bonds, with a variety of conformations possible (see Section 3.3.1). However,... 

Another important factor proved to be the influence of trace quantities of moisture in the compacts, from both the environment and also within the protein itself. Dry proteins adsorb water with avidity because of the exposed hydrophilic regions within the protein structure, changing the properties of the hydrogen bonding within the structure and, therefore, the flexibility of the overall structure. Excessive drying, on the other hand, can result in the collapse of an otherwise water-soluble protein to the point where it is effectively denatured and will no longer dissolve. 

FIGURE 4-15 Globul ar protein structures are compact and varied. Human serum albumin (Mr 64,500) has 585 residues in a single chain. Given here are the approximate dimensions its single polypeptide chain would have if it occurred entirely in extended /3 conformation or as an a helix. Also shown is the size of the protein in its native globular form, as determined by X-ray crystallography the polypeptide chain must be very compactly folded to fit into these dimensions. 

Many soluble native proteins are compact, essentially spherical structures with frictional ratios (///min) around 1.25. (The term f/fmin represents the ratio of the measured frictional coefficient to the minimal value which could be obtained for the equivalent anhydrous sphere. This... 

Part 2, Protein Structure and Function, contains four chapters that relate to the structures and functions of proteins. In chapter 3, The Building Blocks of Proteins Amino Acids, Peptides, and Polypeptides, we discuss basic structural and chemical properties of amino acids, peptides and polypeptides. In chapter 4, The Three-Dimensional Structures of Proteins, we describe how and why polypeptide chains fold into long fibrous molecules in some cases, or into compact globular molecules in other cases. In chapter... 

Another important event contributing to the progress in this field was the development of reaction microcalorimetry, which has permitted direct measurement of heat effects involved with the transfer of hydrophobic substances from a nonpolar environment to water. These processes have been thought to mimic the unfolding of compact protein, structures. Prior to the development of direct calorimetric techniques, all information on the interaction of a hydrophobic substance with water was obtained from equilibrium studies. However, the results were limited in accuracy, particularly those properties that are obtained by consecutive temperature differentiation of the solubility, for example, the change in heat capacity. 

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