Protein Structure

Figure 6.1: Hydrogen bond between hydrogen and oxygen in amide one resonance bond. With permission from Bolterauer, Henkel and Opper (1986).

Proteins have several hierarchical levels of structural organization which determine their dynamic and functional capabilities. Protein primary structure is determined by a sequence of 22 possible amino acids held together by peptide bonds. An amino acid consists of carbon atoms bound to nitrogen atoms (peptide bond) and their attendant side groups. The 22 amino acids found in proteins differ in their side groups although each contains a carbon-oxygen double bond known as "amide 1." Strings of amino acids called "peptides" perform many physiological functions including acting as neurotransmitters and circulating hormones. The amino acids impart specific properties according to the sequence of their incorporation into the peptide string. Amino acids differ in their size depending on their side groups; their molecular weights can range from 75 daltons (a dalton is the mass of a hydrogen atom, a twelfth of a carbon atom) for glycine, to about 200 daltons for tryptophan which contains a double aromatic ring. Functional proteins also range in size: 55 kilodaltons (one kilodalton = one thousand daltons) for tubulin monomers to 630 kilodaltons for thyroglobulin, to several million kilodaltons for protein assemblies which comprise large viruses and infectious agents of certain diseases like psittacosis and lymphogranuloma venereum (Harper, 1969). Thus proteins are comprised of several hundred to millions of amino acids. The precise sequence of amino acids is determined by DNA and they are assembled on ribosomes. A polypeptide "backbone" of 200 amino acids would have 22200 different possible primary structures. The mass required to include one example of each of this number of protein structures would far exceed that of the universe!

Amino acids which comprise polypeptide chains and primary protein structure can form linkages with other amino acids within the polypeptide by hydrogen bonds and disulfide bonds. These linkages cause bending of polypeptide chains into coiled or folded structures which determine protein secondary structure. The most stable and commonly observed secondary structure is a right handed coil called an "alpha helix" in which hydrogen bonds (Figure 6.1) form between an oxygen and a hydrogen separated by 3 or 4 amino acids on the polypeptide chain. Alpha helices can interact among themselves in a protein, stacking in parallel or antiparallel arrangements or forming left handed "coiled-coils." Alpha helices (Figure 6.2) are common occurrences in a wide variety of proteins; tubulin is about 40 percent alpha helix in most circumstances (Dustin, 1978). The alpha helix has been proposed as an important site of energy and information transfer in proteins. Davydov has proposed that the energy of ATP hydrolysis utilized in actin-myosin muscle contraction and many other biological events is conveyed along alpha helix pathways via propagating "solitons" which occur due to enharmonic coupling in the carbon-oxygen double bonds (Section 6.7).

Hydrogen bonds forming among amino acid-side groups on polypeptide chains in parallel result in planar secondary protein configurations called beta-pleated sheets. First proposed by Linus Pauling in 1951, beta pleated sheets may themselves align in parallel, antiparallel or mixed formations.

Alpha helices, beta pleated sheets and other secondary structures interact to define protein tertiary structure, upon which most protein functions depend. Hydrophobic forces, charge distribution, disulfide bridges and secondary structure result in folding into globular regions which define the shape of single protein units. Alpha helix and beta pleated sheets pack into arrangements which help determine the tertiary structural domains which often have specific functions like binding a molecule, or associating with other domains to create larger structures. Assembly of groups of tertiary structure determines quaternary structure, like tubulin subunits assembling into microtubules. Generally, hydrophobic interactions like Van der Waals forces are important in quaternary protein assemblies.

Levels of protein assemblies include, at the simplest level, monomeric enzymes. Weighing from 20 to 90 kilodaltons, these enzymes have a single active site at which specific molecules undergo chemical reactions facilitated ("catalyzed") by the enzyme. Some enzymes may require metal ions, organic molecules or specific cofactors to function. Reduced enzymatic activity can result from occupancy of the active site by molecules resistant to enzymatic action, a phenomenon called "competitive inhibition." Active site binding corresponds with specific conformational states of enzymes.

A more complex system is the oligomeric enzyme, an example of which is the acetylcholine receptor: a four subunit oligomer which is activated by binding of acetylcholine. Being composed of several subunits leads to collective properties which arise from the organization and interactions of the components. Many or perhaps most enzymes are oligomeric with molecular weights ranging from 35 to several thousand kilodaltons. Oligomeric subunits often have two binding sites; one is the active site for its enzyme action and the other is a regulatory site which controls the active site by a change in subunit shape or conformation. Regulatory, or effector molecules can change not only the catalytic site activity on that subunit (allosterism) but also on adjacent subunits (cooperativity). Oligomer subunits may be alike (homopolymers) or different (heteropolymers) and coenzymes may be necessary. A single coenzyme molecule can "turn on" the binding capabilities of multiple subunits within an oligomeric enzyme (Roth and Pihlaja, 1977).

Examples of oligomeric enzymes include glutamate dehydrogenase, composed of six 55 kilodalton subunits forming a complex with approximate dimensions of 100 by 100 by 80 nanometers. An example of a more complex oligomer is aspartate transcarbamylase. It contains six regulatory units of about 34 kilodaltons, each composed of 3 dimers. An additional six 100 kilodalton catalytic subunits are each composed of two trimers. Six zinc atoms are necessary in each of the regulatory subunits. Another cooperative oligomer is hemoglobin, composed of two "alpha" and two "beta" subunits; many other oligomeric enzyme patterns have also been observed. Oligomeric enzyme subunits have cooperative interactions which means that the function of one subunit facilitates the conformational actions of other subunits. In hemoglobin, conditions sufficient for binding of one oxygen molecule to one subunit causes the remaining subunits to bind oxygen more easily.

More complex protein assemblies include cytoskeletal polymers and virus coats. The cooperative interactions of their subunits can lead to information processing and thus to intelligent behavior.

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