FEATURE ARTICLE
Biomolecules and Nanotechnology
Evolution has forced innovative solutions to biomolecular problems. Some may inform the growing field of nanotechnology
David Goodsell
Modern Molecular Machinery
As a consequence of the evolution of life from a single primordial cell, all known living things on earth share a common molecular plan. All living things are made of four basic molecular building blocks: protein, nucleic acid, polysaccharide and lipid. Other small molecules are specially synthesized for specific functions, but the everyday work of the cell is performed by the four basics. The earliest cells chose these materials to the exclusion of others, and subsequent generations of cells, right up to our own, have been forced to work with them.
Two different approaches are taken to synthesize these molecules, resulting in characteristic forms and functions. Proteins and nucleic acids are built in modular form by stringing subunits together based on genetic information. Proteins and nucleic acids may be built in any size and with subunits in any order. This gives remarkable flexibility to the form and function of these molecules.
In contrast, lipids and polysaccharides are built by dedicated machines. Each new type of lipid molecule requires the creation of an entirely new suite of synthetic machines. Likewise, a new suite of machines must be created to build each new type of polysaccharide linkage. The result is that lipids and polysaccharides appear in fewer forms than proteins and are used in much more limited, albeit essential, roles.
Our distant relatives developed a standard for biological information, choosing a particular 20 amino acids to be used in proteins, encoded by five types of nucleotides found in the nucleic acids DNA and RNA. Today, every protein is made of these 20 amino acids (at least initially). In their defense, these primordial cells chose an excellent set of building blocks, including flexible and rigid components, charged, uncharged, acidic, basic and neutral amino acids, large and small amino acids, and several with attractive chemically reactive properties (Figure 3). The amino acids may be used to create proteins with a wide range of properties. These include very flexible proteins with changeable shapes and very rigid cross-linked proteins designed to retain their shape under harsh conditions. Other proteins are highly basic or highly acidic, designed to perform their jobs under extreme acidic or alkaline conditions. Some are covered with carbon-rich groups that repel water and seek out membranes for binding; others have polar surfaces and perform their duties in the watery cytoplasm.
Modular synthesis allows proteins to be built in many shapes and sizes. As a consequence, most of the processes of modern cells are performed by proteins. Evolutionary legacy, however, places several limits on the design of proteins. As noted above, proteins are limited to the 20 components encoded in the DNA genome. Evolution also limits the size of proteins, limits them to aqueous environments and requires that they automatically assemble themselves within the crowded confines of the cell. In spite of these limitations, the breadth of protein form and function in modern cells is remarkable.
The size of a protein is limited by the error rate of the protein-synthesis machinery, which in theory could produce a protein of any length. Missense errors, which misread the genetic information and substitute an incorrect amino acid at one position, occur at an average frequency of about 1 in 2,000. For a protein composed of 500 amino acids, one out of four proteins will typically have an error, but nearly every protein of 2,000 amino acids will have one. More important, however, are processivity errors, which cause protein synthesis to abort prematurely. These errors have been estimated to occur at a rate of about 1 in 3,000, so long proteins of several thousand amino acids are only rarely constructed in full. The average size of a typical protein chain, 300 to 500 amino acids, is the compromise adopted by most cells. Error rates keep the chain length low, so larger proteins must be built as complexes of multiple protein chains.
Proteins were invented in "warm, salty pools," so life on earth now requires a warm, aqueous environment (either externally or carried around inside). Water is essential for protein structure and function because of an emergent property of water solutions, termed the hydrophobic effect. Water has peculiar properties, which are used to great advantage by biological molecules. Portions of a protein that are rich in carbon interact weakly with water and are termed hydrophobic. When placed in solution, these hydrophobic regions crowd together in a globule, minimizing contact with water and allowing the water to escape and interact with more favorable environments. The hydrophobic effect is a major stabilizing force for protein folding, where carbon-rich portions of the chain are folded within the protein globule (as well as for formation of the lipid membranes that surround every cell, where the carbon-rich portions of the lipids are packed inside the membrane). Because our molecules rely on hydrophobicity for their structural integrity, we could never live in vacuum or in organic solvents. Our proteins simply would not fold.
Perhaps the most difficult limitation to overcome is the need for self-assembly. Biological molecules are designed to assemble themselves within cells: Proteins are created as unstructured, linear chains of amino acids that must fold into a stable, functional conformation (sometimes with a little chaperoning in the proper direction). Often, the folded chain spontaneously associates with others to form larger stable complexes. This is a major limitation to the design of proteins: Not only must the protein be functional in its active conformation, but the protein chain must also be designed to fold into this active conformation using only the folding tools available in the cell.
» Post Comment