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Bobby WorldWide Approved AAA A layperson's guide to bioenergetics

This page forms part of a joint project between the Faculty of Performance, Visual Arts and Communications and the School of Biochemistry and Microbiology at the University of Leeds, that will devise live and virtual choreography stimulated by research into the production and utilisation of Adenosine Triphosphate (ATP). Engaging with the public is an important motivation for this project, so it is appropriate to identify those key scientific concepts which will illuminate discussions between scientists and dancers, some of which we hope to communicate to a wider audience.

Adenosine triphosphate (ATP), a relatively small molecule containing about 45 atoms, is fundamental to life. It is a major constituent of every living cell, where it is continuously broken down and re-synthesised to transmit the energy that drives the machinery of life. These processes have continued with little alteration for thousands of millions of years, although most individual ATP molecules survive within our bodies for only a few seconds. A young active person breaks down and rebuilds their own body weight in ATP every day.

ATP was first identified in 1929, but details of its manufacture and utilisation have only gradually been uncovered, leading to the award of several Nobel prizes. Our recent rapid progress is a cause for celebration.

ATP commonly delivers its energy when it is split or "hydrolysed" by a water molecule into two fragments of unequal size: adenosine diphosphate (ADP) and inorganic phosphate (Pi). It is regenerated by forcing these two fragments back together again. It isnít necessary to rebuild the entire molecule from scratch, merely to re-attach the phosphate group. Each individual ATP molecule releases only a tiny amount of energy when it is broken down in this way, but we use billions of them every second, so the total yield may be considerable.

Although small, the energy available from splitting ATP is normally larger than the random thermal vibrations that continuously disturb the molecules in all living organisms. The energy from ATP breakdown is applied throughout the living world whenever it is needed to nudge some process in a productive direction, at millions of individual locations within millions of individual cells. ATP hydrolysis gives an overall impetus and a sense of direction to life. It is often compared to money: "ATP is the energy currency of the cell".

Movement in living cells is produced by a huge variety of molecular motors, most of which are powered by ATP. The force produced by each individual motor is tiny, so millions are frequently harnessed together to achieve a useful result. This is particularly the case in our voluntary muscles, which are built from millions of very long thin cells. Muscle tension is generated when a large protein called myosin tugs against a delicate intracellular framework, largely composed of another smaller protein called actin. The X-ray structure of the myosin motor domain has been intensively studied.

animated cartoon showing myosin head groups pulling against an actin failamentWithin each muscle cell, the myosin molecules are organised into millions of teams, called thick filaments, each team containing a few hundred members. The actin is also organised into ropes called thin filaments, which lie between the thick filaments. When the signal is given to contract, the "head groups" from individual myosin molecules grab hold of the actin ropes, and pull themselves along by a short distance. The energy to do this derives from the breakdown of ATP. When this minute tug has been delivered, each myosin head must detach from the actin rope, simultaneously splitting a fresh molecule of ATP, so that it can re-attach for the next pull a little bit further along the rope. [myosin head group animation taken from the MRC Cambridge muscle web pages]

animated cartoon showing muscle shorteningOpposite ends of each myosin team face in opposite directions, so that instead of "rowing" their entire thick filament along to the far end of the cell, their efforts pull the whole actin framework closer together, thereby shortening the cell. [sarcomere shortening diagram from Professor Mike Firenczi]

ATP does far more than merely power muscle contraction. It is a universal cellular power supply that drives a sophisticated industrial plant, containing a multitude of microscopic assembly lines, complete with pumps, cleaners, copiers, cookers, transport and signalling systems, and maintenance engineers.

Electron microscope picture of a typical mitochondrionMost of the ATP required by our cells is generated by hundreds of specialised sub-cellular "organelles" called mitochondria (singular: mitochondrion). These minute structures, one thousandth of a millimetre across, contain most of the respiratory enzymes which process our food, consuming oxygen and generating carbon dioxide, which we eventually breathe out. Mitochondria evolved about two thousand million years ago from free-living bacteria, which formed a close symbiotic relationship with our distant ancestral cells.

Each mitochondrion is surrounded by two delicate oily membranes, which are only about five millionths of a millimetre across at the narrowest point. The interior of each organelle is sealed off from the remainder of the cell, and is known as the matrix space. The inner membrane must remain intact for the mitochondrion to work, and if it is damaged then the organelle will fail. As the mitochondrion consumes oxygen, specialised molecular pumps within the inner membrane transfer positively charged protons (the nuclei of hydrogen atoms) from the inside to the outside of the membrane, thereby generating a electrical voltage across the inner membrane. The oxidation and pumping system within the inner membrane is known as the respiratory chain.

This trans-membrane voltage, or mitochondrial membrane potential, is about 150 millivolts (one tenth of a torch battery) but it is developed across an extremely thin membrane, so that the individual biomolecules involved in this process experience an electrical stress of about 30 million volts per metre. These resilient molecules out-perform the high-voltage transformer oil that is used to insulate power stations and the National Grid.

cartoon of the ATP synthetic machineryBecause of the "huge" electrical voltage across the mitochondrial inner membrane, the protons that were expelled by the respiratory chain are drawn again towards the interior. As they re-enter the organelle by a different route, they are obliged to work a molecular turbine called the F0 motor, that is embedded in the membrane. The protons turn a tiny protein crank and force it to rotate as they re-enter the mitochondrial matrix space.

This molecular cranking action is fundamental to the manufacture of ATP. All major groups of living species (plants, animals and bacteria) are dependent on this protein. As far as we can tell, it is the most active enzyme in the universe.

Also attached to each F0 motor by a protein bracket is a large F1 head group which projects into the interior of the mitochondrion. Each mitochondrial membrane contains many thousands of these assemblies, which are just large enough to see with an electron microscope. The X-ray structure of the F1 head group was solved by John Walker's group in Cambridge, confirming an earlier theory by Paul Boyer about the way the enzyme worked. This resulted in the award of a Nobel prize in 1997. In the same year Noji et al in Japan devised an ingenious method to visualise the enzyme while it was working and were able to see the moving parts rotate. The manufacture of ATP is an amazing chemical feat (somewhat equivalent to making water run uphill) which is achieved in the following manner.

animated cartoon of the ATP synthetic mechanismEach F1 head group consists of three catalytic assemblies, which operate sequentially but out of step with each other, like three musicians performing an endless canon. Their movements are dictated by the rotating crankshaft that lies between them, forcing them to move as the shaft rotates.

Each assembly, working in turn, binds one molecule of ADP and one of phosphate. These reluctant partners normally repel one another, but they can be induced to join together because the F1 proteins actively embrace them, cuddling them, easing their union, and avidly binding to the resulting ATP. The problem is to make the protein let go.

The rotation of the crankshaft is vital for this. By forcing itself against each catalytic assembly in turn, the crank obliges the F1 proteins to change their shape, and release the finished ATP into the mitochondrial interior. Yet another mitochondrial protein trades each completed ATP for an incoming ADP across the mitochondrial membrane.

animated cartoon showing the endless recirculation of ATP and ADP between mitochondria and the remainder of the cell

We believe that we can dance these processes, not in a strictly representational manner, but in a way that will convey the fundamental scientific concepts to a wider audience. Bio-molecular assemblies share the following characteristics, all of which can be illustrated and interpreted through dance:

* Molecules prefer the company of their own kind: the oily ones stick together, as do the water-loving electrically-charged varieties, but these two main classes avoid each other whenever possible. Living cells exploit this contradiction with 'forced marriages' between reluctant partners. The creative tension that results is a major driving force for life.

* All these molecules continuously twist and writhe into varied conformations, only some of which are productive. If they get it 'wrong' then they re-group and Ďtry againí. These random trials may cause significant delay, and often limit the maximum speed of living processes.

* There is a notion of 'induced fit' whereby large molecules change their shape to accommodate another molecule that has just arrived. We also see cooperative and anti-cooperative behaviour.

* Random external perturbations arise from thermal motion. These range from minor events, scarcely detectable, to molecular 'earthquakes' that threaten the integrity of the whole ensemble. At a molecular level many living processes resemble life itself: chaotic in nature, like seaweed tumbled by the waves, but nevertheless there is purposeful motion with an overall sense of direction.

HTML and text by John Illingworth