They are tiny, and there are billions of them inside you. Tiny machines, one thousand times thinner than a hair strand but strong enough to carry all kinds of material within your cells. Yes, there is a complex army of tiny machines inside your body performing an amazing array of functions while you sit at home sipping your tea.

Your heart is beating. Its lifelong duty is to pump blood to tissues to deliver essential nutrients. Transportation of nutrients continues from blood vessels to cells and then into subcellular compartments. Inside of a cell, there is a need for sophisticated biomachines which are responsible for transport. Did you know that you were equipped with minuscule motors that transported cargos in your cells? Or about cellular highways where molecular cargos are transported?

There are various proteins called “motors” in the cell. They can convert chemical energy to mechanical energy to produce force and motion in the cellular highways.¹ Amazingly, molecular motors are much superior to man-made motors in terms of energetic efficiency by hydrolyzing ATP to fuel enzymatic reactions. These molecular motors include rotary motors, polymerization motors, nucleic acid motors and cytoskeletal motors.

Rotary motors

Bacterial flagellum, used for swimming, acts as a propeller and uses a rotary motor. It has been suggested that this motor is similar to Fo motor found in FoF1-ATP synthase. FoF1-ATP synthase takes part in the conversion of chemical energy in ATP to proton gradient, or vice versa. This chemical reaction involves mechanical rotation of parts of the complex.

Polymerization and nucleic acid motors

Polymerization motors take role in polymerizations and these polymerizations generate forces for repulsion (Actin or microtubule polymerization), or separation of clathrin buds from plasma membrane (Dynamin).

DNA and RNA synthesis also involves the use of molecular motors such as RNA polymerase (RNA synthesis from DNA), DNA polymerase (DNA synthesis), Helicases (separation of double stranded DNA prior to DNA or RNA synthesis), Topoisomerases (removal of supercoiling of DNA), RSC, SWI/SNF, and SMC proteins (Chromatin remodeling and chromosome condensation). Moreover, there are specific viral DNA packaging motors that pack tightly viral DNA into capsids. separation of double stranded DNA prior to DNA or RNA synthesis), Topoisomerases (removal of supercoiling of DNA), RSC, SWI/SNF, and SMC proteins (Chromatin remodeling and chromosome condensation). Moreover, there are specific viral DNA packaging motors that pack tightly viral DNA into capsids.

Cytoskeletal motors

Dyneins, kinesins and myosins denote the three major classes of molecular motor that moves along cytoskeletal structures. Myosin is among the most prominent of motor proteins that takes role in muscle contraction. Kinesin operates on microtubules (long tubes composed of dimers of the protein tubulin, arranged to form 13 parallel tracks) to move cargos inside the cells away from the nucleus (toward positive end of microtubules) and play essential roles in the formation of spindle apparatus and axonal transport. Dynein is also known to transport cargo but in the opposite direction to Kinesin, towards the cell nucleus (toward minus end of microtubules). In addition, dynein is required to beat cilia and flagella.

How molecular motors move

Myosin and kinesin are structurally similar in terms of being dimeric with two motor heads, two legs, and a common stalk. The head regions control the forward movement by binding itself to actin or microtubule filaments. Movement is facilitated by the consumption of ATP by ATPase sites. It is fascinating how these motors translate chemical energy into motion and still be different to the movement of cars. There are different proposals as to how molecular motors move, such as walking (hand-over-hand model), inchworm model, and biased diffusion model.

The-hand-over-hand model suggests that ATP binding induces a conformational change in the forward head movements and keeps fixed, thus leading to the movement of the rear head forward and vice versa. This model, which is also known as the walking model, is similar to upright walking where one foot moves forward while other stay fixed, and vice versa. On the other hand, the inchworm model suggests that only forward head movements use ATP and leads while the other head follows. Studies on the Myosin VI with shorter legs suggested a biased diffusion model. In the diffusion model, the motor moves randomly to the next binding site in a forward direction. In order to find out which mechanism used by molecular motors, scientists measured how much of the head moves following staining with a fluorescent dye. Since molecular motor movements are so small (5-10 nM), optical traps and cantilever probes (>100 μm) were not useful to watch head movements. By increasing both photostability and brightness of organic dyes, Dr. Yildiz at UC Berkeley was able to measure head movements down to 1.5nM scale.

Kinesin: A molecular motor that walks

Kinesins are among microtubule-based motors recently shown to walk like a mountain climber by swapping its two motor units (analogous to feet) in a hand-over-hand mechanism rather than an inchworm mechanism. This recent discovery sheds light on how kinesin moves its cargos such as membrane components, messenger RNA, signaling moleculers, and others along microtubules. In addition, as suggested by findings of Dr. Yildiz, kinesin demonstrates an asymmetric walking where motor heads alternate with slow and fast steps. Further studies using advanced microscopy techniques (called FIONA) which allow nano scale detection of movement down to 2nM resolution demonstrated delicately that processive kinesin motor takes about 8 nM steps (eight-billionths of a meter) for each ATP molecule consumption with alternating 16-nm and 0-nm steps. Furthermore, kinesin is attached to the microtubule while it waits for ATP between steps. Since kinesin is used for long distance cargo transport on relatively big highways of a cell, it elegantly demonstrates a processive motor that reliably travels in a coordinated manner. Of course, not all motors will be moving like kinesin.

Dynein moves through uncoordinated stepping of ring domains

Another motor protein involved in long distance cargo transport is dynein. Dynein is a staggering giant which is much bigger and complex than kinesin and myosin motors. There are about 15 types of dyneins known to take role in cilia and flagella movement and 2 cytoplasmic forms. Cytoplasmic dynein is a homodimeric AAA+ (ATPases associated with cellular activities) motor that transports toward the microtubule minus end, acting opposite to kinesin. FIONA assay demonstrated that the heads moving processively but independently. This mechanism is quite different from the hand-over-hand stepping of kinesin and myosin, for dynein’s steps are not strictly coordinated and highly variable. Most of the time, dynein heads move alternatively with variable head-to-head distance of about 5-50nM. Each head of dynein mostly does not pass each other.

Elegant design, efficiency in transportation and being part of the living system makes molecular motors in the cells superior to man-made motors. Molecular motors travel on cellular highways in the cellular microcosm in the manner of dutiful officials of a king traveling in his domain in security via the fastest modes of transportation and easily cross provincial boundaries, demonstrating more evidently that the Sovereignty of the Eternal King is limitless. Indeed, the signs of His Dominion are reflected by each and every entity from the microcosmic world to macrocosmic universe.

Note

1 Cellular highways are composed of microtubules, microfilaments and actin filaments. Myosin moves along microfilaments through interaction with actin, but dynein and kinesin move along microtubules through interaction with tubulin

References

• DeWitt MA et al. Cytoplasmic dynein moves through uncoordinated stepping of the AAA+ ring domains. Science. 2012 Jan 13;335(6065):221-5. Epub 2011 Dec 8.
• King SM. AAA domains and organization of the dynein motor unit. J Cell Sci. 2000 Jul;113 ( Pt 14):2521-6.
• Wilhelm J. Walter & Stefan Diez. A staggering giant. Nature. Vol 482. 2 February 2012.
• Molecular motors and Motor proteins. Retrieved from Wikipedia on 3/31/2012.
• Yildiz et al. Myosin V Walks Hand-Over-Hand: Single Fluorophore Imaging with 1.5-nm Localization. Science 27 June 2003:Vol. 300 no. 5628 pp. 2061-2065
• Yildiz et al. Kinesin Walks Hand-Over-Hand. Science 30 January 2004: Vol. 303 no. 5658 pp. 676-678

At the same time as these events are happening almost simultaneously, information from my eyes and my finger is being sent to the brain so that my finger will move in the way I expect it to. For example, if the path of my finger’s movement is somehow blocked, my brain can redirect it.

However, the event described above is not that simple. Starting from the neurons and continuing until we reach the muscles, every element that acts during this process displays extraordinarily complex alterations at both cellular and molecular levels.

Consider muscle cells, since they are moderately well understood. Upon arriving at the muscle cell, the electrical impulse causes the voltage-sensitive calcium channels in specific compartments within the cell to open and release calcium into the cell. You might remember from high school biology that muscle contraction is the result of two proteins (myosin and actin) sliding over each other. Normally, actins are masked by proteins known as tropomyosin. During the waiting period, therefore, the interaction between myosin and actin, which leads to contraction, cannot occur. This is why the muscle cell releases calcium, for when calcium is free in the cell, it binds to tropomyosin and enables it to move. As a result, actin is free to interact with myosin.1

After that, millions of molecules containing energy, known as ATP, bind to millions of myosin proteins, and the muscle contracts. When the contraction ends, the freed-up calcium is stored once again in specific compartments. When calcium is not present, tropomyosins again mask the actin proteins, and millions of muscle cells revert to their initial position, ready to respond to another contraction.

I realize that all of this is hard for the average reader to understand. However, the events that take place are even more complicated.

Expressions like “ATP binds to myosin” and “calcium is stored in compartments” are, in fact, simplified ways of explaining a highly complex event. Since there is a reason for everything, our cells should contain something that is performing these functions and carrying out such events. If we expand this problem to its limits, we will have to understand that each cell contains a large set of rapid and specific chemical reactions that occur constantly and yet do not interfere with one another. Based on current scientific knowledge, we can say that enzymes conduct almost all reactions in a cell, and that DNA has all the necessary information to produce enzymes. Enzymes are protein molecules that speed up and regulate all of the reactions that take place in a cell. If there were no enzymes, the reaction that a cell carries out in seconds could only be completed in thousands of years, and consequently, life as we know it would not exist. Life requires that the correct enzyme be found in the correct place and at the correct concentration.

Based on this, let’s revisit the above example. When the electric impulse reaches the muscle cell and calcium ions are released, this and every external and internal signal is conveyed to the DNA through a mechanism that we are just beginning to appreciate: signal transduction. Later, RNA is produced in those regions of the DNA that are responsible for producing the enzymes that enable the cell to give the appropriate answer (RNA helps DNA to produce enzymes). The synthesis of the enzyme is regulated at various checkpoints, such as during RNA production or RNA translocation out of the nucleus by other enzymes.2 ATPase, one of the many enzymes produced, makes it possible to use ATP, while another enzyme makes sure that the ATPases are in the correct location in the cell. Meanwhile, in order to sustain life, thousands of other enzymes conduct various reactions at the correct time and place. Therefore, when I move my finger, the number of active elements increases enormously.

Let’s look at the finer points of the cell. Using a simple calculation, in which each number is much smaller than the actual number used, if we assume that one million cells perform some kind of action from the reception of the first impulse in the brain until the time the muscle contracts, and if we calculate that one thousand reactions occur in each of these cells, this means that one billion reactions are performed for the simple action of moving a finger. One billion reactions, in just one second. And at the same time, my heart is beating, new blood cells are being produced, my eyes are sending visual information to my brain, my kidneys are filtering my blood, my lungs are exchanging old air with new, fresh air, my digestive system is supplying the necessary nutrients to my blood stream, and much, much more. Moreover, all of these are continually taking place. The fact that all of these actions are occurring, again based on a very rough and simple calculation, means that maybe one trillion reactions are occurring every second. As a result, a person might feel that it is quite possible, at any instant, for this perfect machine-the human body-to fall apart.

Realizing this, one might actually find it hard to believe that he or she is really alive. For example, I would never believe that such a machine would work if I did not have the empirical knowledge that it does work. How, for example, can I believe that I can produce one trillion reactions every moment and never confuse one with another, that it takes one billion reactions to move my finger, and that one trillion gears are working by themselves without making any mistakes?

With this idea in mind, I see the following lines in Epitomes of Light: “Also, since a building that contains every kind of artwork and riches cannot exist without having been built by someone, the existence of this universe is intimately connected with the existence of the Builder. If someone thinks carefully, it is impossible to accept one without the other.”3 Upon reading these words, I start to realize that all of these gears are not working by themselves, but rather that every second all of the trillion gears are being regulated by the One for whom nothing is difficult.

Suddenly, I remember that whenever the names of God are recited, I hear the name al-Hayy right next to al-Qayyum: God is He besides Whom there is no god; He is al-Hayy (the Ever-Living), al-Qayyum (the One Who sustains and protects all that exists) (Qur’an 2:255). Putting al-Qayyum next to “life” indicates, at least to me, that every living being is kept alive at each instant by al-Qayyum. If His control over each person’s existence were to be lost for even one second, one trillion gears would become irreversibly mixed up and the body would fall apart instantly. While thanking God for all that He has given me, I realize that I cannot thank Him enough for even one gear.

References

1. Harvey Lodish et al., Molecular Cell Biology, New York: Scientific American Books, c1995, 1027-29.
2. Lewin, Benjamin, Genes VI, Oxford, NY: Oxford University Press, 1997, 847.
3. Nursi, S., Epitomes of Light: Mathnawi al-Nuriya: The Essentials of the Risale-i Nur, Kaynak A.S., 1999.