The World’s Smallest Machines

The steady increase in microprocessor speeds over the past several decades has been driven by the ability to make smaller and smaller features on the surface of silicon. Related microfabrication technology has enabled the construction of miniature machines with gears only one-tenth of a millimeter in diameter. For example, engineers in a U.S. government security lab have recently unveiled a tiny, nickel-sized robot. Nonetheless, machines made by man are still gargantuan and clumsy compared to the molecular machines that operate in every living cell.

These amazing machines are proteins only a few nanometers (billionth of a meter) in size, yet they perform the myriad tasks necessary to keep a cell alive. For example, the protein kinesin carries cargo along microtubule "highways" in a cell, while the protein myosin produces the contraction of muscle cells. Over the past decade, biophysicists have developed new experimental techniques that may explain how these molecular motors actually work.

One of the most amazing molecular machines is DNA polymerase, a protein that replicates DNA by adding bases as it moves along the template strand. Sequencing the three billion nucleotides in the human genome was a monumental endeavor. Even with a worldwide collaboration, it took over a decade to complete. Yet a few dozen DNA polymerases in a human cell can read and make a new copy of the entire genome in less than a day. Despite our advanced technology, we still lag far behind Mother Nature.

A DNA polymerase can copy 30,000 bases per minute, with an error only once in a billion bases. A typist with this speed and fidelity could copy an issue of The Economist in three minutes, and make a mistake only once every 10,000 issues. The polymerase achieves its phenomenal level of accuracy by carefully monitoring the bases it has already added. If an imperfect match is detected, the polymerase undergoes a structural change that allows it to move backwards and remove the incorrect bases. Thus the tiny DNA polymerase is a multi-function machine able to read the sequence of bases, replicate the matching strand, as well as identify and correct errors. Amazingly, these functions are powered by individual nucleotides in solution, the very building blocks that are used to construct the nascent strand of DNA. Energy is liberated because the DNA polymerase replaces a high-energy bond in the nucleotide with a more stable bond in the DNA strand.

In the past, it was necessary to study millions of these molecular machines simultaneously, so that many of their most fascinating properties were obscured. Biophysicists have recently obtained new insight into DNA polymerase, as well as many other molecular motors, by watching single molecules in action. Now it is possible to play tug-of-war with a single DNA polymerase by attaching one end of a DNA strand to a micron-sized bead trapped by a focused laser beam. As the DNA polymerase replicates the DNA it pulls the bead out of the focus. The position of the bead gives both the polymerase’s rate of replication and pulling force. Researchers in the laboratory of Professor Carlos Bustamante at the University of California, Berkeley performed this experiment, and found that the DNA polymerase was able to pull with a force of over 30 pN (30 millionth millionths of a Newton). Imagining the polymerase enlarged to human size helps one appreciate its Herculean ability: with the same force-to-mass ratio a human could lift ten billion metric tons, or the weight of about 200 aircraft carriers. This makes even Superman look like a weakling.

Besides being a marvel, these single-molecular motor experiments have suddenly allowed biophysicists to explore variables (such as force) that were previously inaccessible. An improved understanding of protein machines will help explain the inner workings of the cell, and may someday allow humans to compete with nature’s ingenious molecular machines.