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This schematic illustration shows a series of hydrogen deposition tools (above) placing hydrogen atoms on a series of cylindrical work pieces (below). The two belts move from left to right, carried and brought together by two rollers (atomic detail not shown). Hydrogen atoms are shown in white, except for those undergoing transfer, highlighted with stripes. The deposition tool is a diamondoid cage structure ending in a hydrogen-tipped silicon atom. The cylindrical workpieces initially have four carbon radical sites, one of which receives the added hydrogen. Because carbon binds hydrogen more tightly than does silicon, the hydrogen atoms transfer reliably. ©1993 K. Eric Drexler. All rights reserved.
A landmark event in biology occurred this past summer when researchers at the University of Bath published a map, at atomic resolution, of the molecular motor responsible for muscle action. [Ivan Rayment, et al., Science 261:50-57; and Science 261:58-65, 2July93]. This motor, called "myosin subfragment-1" or "S1", is the portion of the myosin molecule that converts chemical energy into force and motion.
S1 contains more than 50,000 atoms and is shaped like a whale about 5 nm wide at the head and 19 nm long. The head contains two active sites: a nucleotide binding pocket where ATP molecules are trapped and tapped for energy to run the motor; and an actin-binding site where the myosin head interacts with a protein filament called actin. The myosin tail is permanently connected to a myosin filament. Myosin filaments are densely studded with S1. In intact muscle, arrays of myosin and actin filaments interdigitate with each other. Where actin and myosin filaments overlap, they are bridged by the S1 motors.
During muscle contraction the motors travel along actin filaments pulling their myosin filament along in 5 nm steps -- like a line of whales joined to a thick rope by their tails, grabbing and releasing another rope with their mouths, flexing and unflexing their bodies to reposition themselves. Decades of microscopy and biochemical studies had already provided a picture of muscle mechanics at this level of detail. The amino acid sequences of the proteins have long been known, and the actin molecule was mapped in detail several years ago. A mechanical understanding of the system, however, has waited for a map of the myosin motor.
Mapping S1 was not a straightforward task. For 30 years the molecule has resisted efforts to crystallize it for X-ray diffraction mapping. The Bath researchers circumvented this problem by chemically modifying some of the amino acids on the molecule's surface. Other technical problems were overcome only after prodigious chemical and computational efforts.
The 3-D map of the myosin motor, although it is a view at only one moment in the contractile cycle, gives a rough indication of how the motor works:
An energy-bearing ATP molecule is captured at the nucleotide binding pocket when the pocket is open -- this happens to be when the motor is tightly bound to its actin filament. The ATP capture causes a movement in molecular domains beneath the site, opening a cleft at the front end of the head -- like the opening of a whale's mouth -- and causing S1 to release its hold on the actin filament. (It may remain weakly attached by a flexible peptide loop.) The pocket now closes upon the nucleotide, and a bend develops in the myosin tail. Crunch! -- the terminal phosphate is severed from the ATP. The products of this hydrolysis reaction, ADP and phosphate, remain stuck in the reaction pocket for now. The myosin head again approaches the actin filament and weakly binds with it, altering intramolecular stresses. Domains shift, closing the cleft at the actin-binding site and partially opening the nucleotide binding pocket; the severed phosphate is released. Now the myosin head can bind more tightly to actin. When it does, the tight binding state triggers the power stroke in which the bent myosin tail is allowed to straighten, converting its stored energy into force and motion. Finally, in the straightened configuration, the binding pocket fully opens, releasing ADP.
Five years from now, this rough and still rather speculative verbal description of the actin-myosin contractile cycle will probably have become a hundred times more detailed, and correspondingly hard to follow. But by then I hope someone will have created an animated stereoscopic computer model that will fully reveal the workings of this motor in terms we can understand intuitively.
I can think of no more effective way to allay the fears many people have about bioscience and nanotechnology than to demystify the workings of molecular motors. If the subject of automobile engines were as arcane and impenetrable for the average person as molecular biology is today, we would have jeremy rifkins trying to outlaw the use of cars. The mechanical aspects of molecular systems are the keys to public understanding and enthusiasm, and we are finally coming close to having those keys in hand.
Dr. Russell Mills is research director at a company in California.
|Foresight Update 17 - Table of Contents|
The Third Foresight Research Conference on Molecular Nanotechnology: Computer-Aided Design of Molecular Systems attracted about two hundred participants to Palo Alto on October 14-16, 1993. The other academic/nonprofit sponsors, besides Foresight Institute, were the Stanford University Department of Materials Science & Engineering, the Molecular Graphics Society, and the Institute for Molecular Manufacturing. (See list of conference speakers.)
Besides the listed speakers, attendees had the opportunity to look at and discuss posters; attend demonstrations and exhibits; and hear panel discussions on "Can Today's Computational Chemistry Model Tomorrow's Molecular Machines?", "Molecular Nanotechnology: Status and Next Steps", and "General Purpose Molecular Manufacturing: How Long?"
Conference proceedings are being published as a special issue of the journal Nanotechnology, published by the Institute of Physics. Watch this publication for details on ordering the issue.
A day-long pre-conference tutorial was held October 13 on the subject "Introduction to Modeling Molecular Systems for the Computer Scientist". The thirty participants attended the following sessions:
|K. Eric Drexler||Computational Methods for Molecular Manufacturing|
|Ralph C. Merkle||Design Issues in Self Replicating Systems|
|William A. Goddard III||An Introduction to Computational Chemistry|
|Biosym||Methods & Applications in Density Functional Theory|
|Peter Kollman||An Introduction to Molecular Mechanics|
|Ralph C. Merkle||Computational Nanotechnology|
The conference received corporate sponsorship support from Apple Computer, Beckman Instruments, Xerox PARC, ARCO, Biosym Technologies, Digital Instruments, Fenwick & West, JEOL, Nanoscale Progress, and Niehaus Ryan Haller Public Relations.
|Introduction to the Design of Molecular Systems
Eric Drexler, Institute for Molecular Manufacturing
|Modeling Mechanochemical Processes
Charles Musgrave, California Institute of Technology
Ralph Merkle, Xerox Palo Alto Research Center
|Modeling Diamond CVD with Density Functional Theory
Warren Pickett, Naval Research Laboratory
|Modeling the Design of Proteins
Ken Dill, University of California at San Francisco
|Atom Manipulation by Proximal Probes: Experiment and Theory
Makoto Sawamura, Aono Atomcraft Project, Japan
William Goddard III, California Institute of Technology
Scientific Visualization for Scanning Tunneling Microscopy (STM)
Russell Taylor, Univ. of North Carolina at Chapel Hill
|Crystal-Based Molecular CAD
Geoff Leach,Royal Melbourne Institute of Technology
|Ab Initio Methods and Software
Charles Bauschlicher, NASA Ames
|Packing Molecular Building Blocks
Markus Krummenacker, Institute for Molecular Manufacturing
|Nanocomputers and Reversible Computation
J. Storrs Hall, Rutgers University
|Visualization with Molecular Graphics
Michael Pique, Scripps Research Institute
|Computational Chemistry, Parallel Supercomputers & Nanotechnology:
Current Capabilities and Future Progress
Ian Foster and Rick Stevens, Argonne National Laboratory
|Mechanical Engineering CAD
Joel Orr, Orr Associates, Inc.
|INVENTON: An Automated Molecular Invention System
Applied to Problems in Nanotechnology
Michael Pitman, UC Santa Cruz
|Molecular Building Blocks
Ted Kaehler, Apple Computer, Inc.
|(above) Geof Leach and Ralph Merkle present the results of their collaboration on Crystal Clear, the first nanotechnology CAD program.|
|(left) Prof. Ken Dill of the University of California at San Francisco explains the state of the art in designing and modeling proteins, the chief building blocks of natural molecular machinery.|
|Markus Krummenacker, Makoto Sawamura, Martin Edelstein, Eric Drexler, and Ted Kaehler debate development strategies on Friday's panel "Molecular Nanotechnology: Status and Next Steps."|
|Russ Taylor of North Carolina is mobbed with questions after his talk on virtual reality for interacting with the nanoscale world.|
|Jim Lewis, Tom McKendree, Josh Hall, and Neil Jacobstein discuss the critical question: "General Purpose Molecular Manufacturing: How Long?"|
|Makoto Sawamura describes progress toward atom manipulation in Japan's Aono Atomcraft Project.||Rick Stevens of Argonne National Lab sketches his and colleague Ian Foster's work on the intersection between computational chemistry, parallel supercomputing, and nanotechnology.||J. Storrs Hall of Rutgers University's Laboratory for Computer Science Research describes energy-efficient computation based on nanotechnology. In addition to his research, Hall moderates the Internet nanotechnology discussion group sci.nanotech.|
From Foresight Update 17, originally published 15 December 1993.
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