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Protein design as a pathway to molecular manufacturing

The first journal article on molecular nanotechnology, reproduced here by permission of the author.

Special thanks from IMM to Jim Lewis for preparing this Web document and writing the following introduction to the paper:

Presented here is the complete text of the landmark paper that K. Eric Drexler published in the Proceedings of the National Academy of Sciences USA in 1981. In this paper he advanced the proposal that the molecular machinery found in living systems demonstrates the feasibility of doing advanced molecular engineering to produce complex, artificial molecular machines. A key insight is his proposal that the engineering problem of designing proteins to fold in a predetermined way is much easier than the scientific problem of predicting how natural proteins fold. Appended to this paper is a short perspective written by Drexler in 1988 in which he notes substantial progress made in the area of protein structure design compared to protein structure prediction.
--Jim Lewis

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  • Title, abstract and introduction
  • Protein design
  • Molecular machinery
  • Firmness of the argument
  • Applications to computation
  • Some biological applications
  • Implications for the present
  • Conclusion
  • References
  • Perspective from Drexler 7 years later

    • PUBLISHED IN 1981 IN:

    Proc. Natl. Acad. Sci. USA
    Vol. 78, No. 9, pp. 5275-5278, September 1981
    Chemistry section

    Molecular engineering:

    An approach to the development of general capabilities for molecular manipulation


    KEY WORDS: molecular machinery/protein design/synthetic chemistry/computation/tissue characterization

    K. Eric Drexler


    Space Systems Laboratory, Massachusetts Institute of Technology,
    Cambridge, Massachusetts 02139

    Communicated by Arthur Kantrowitz, June 4, 1981

    ABSTRACT: Development of the ability to design protein molecules will open a path to the fabrication of devices to complex atomic specifications, thus sidestepping obstacles facing conventional microtechnology . This path will involve construction of molecular machinery able to position reactive groups to atomic precision. It could lead to great advances in computational devices and in the ability to manipulate biological materials. The existence of this path has implications for the present.

    FEYNMAN'S 1959 talk entitled "There's Plenty of Room at the Bottom" (1) discussed microtechnology as a frontier to be pushed back, like the frontiers of high pressure, low temperature, or high vacuum. He suggested that ordinary machines could build smaller machines that could build still smaller machines, working step by step down toward the molecular level; he also suggested using particle beams to define two-dimensional patterns. Present microtechnology (exemplified by integrated circuits) has realized some of the potential outlined by Feynman by following the same basic approach: working down from the macroscopic level to the microscopic.

    Present microtechnology (2) handles statistical populations of atoms. As the devices shrink, the atomic graininess of matter creates irregularities and imperfections, so long as atoms are handled in bulk, rather than individually. Indeed, such miniaturization of bulk processes seems unable to reach the ultimate level of microtechnology -- the structuring of matter to complex atomic specifications. In this paper, I will outline a path to this goal, a general molecular engineering technology. The existence of this path will be shown to have implications for the present.

    Although the capabilities described may not prove necessary to the achievement of any particular objective, they will prove sufficient for the achievement of an extraordinary range of objectives in which the structuring and analysis of matter are concerned. The claim that devices can be built to complex atomic specifications should not, however, be construed to deny the inevitability of a finite error rate arising from thermodynamic effects (and radiation damage). Such errors can be minimized through the use of free energy in error-correcting procedures (including rejection of faulty components before device assembly); the effects of errors can be minimized through fault-tolerant design, as in macroscopic engineering.

    The emphasis on devices that have general capabilities should be taken in the spirit of early work on the theoretical capabilities of computers, which did not attempt to predict such practical embodiments as specialized or distributed computation systems. The present argument, however, will proceed from step to step by close analogies between the proposed steps and past developments in nature and technology, rather than by mathematical proof. We commonly accept the feasibility of new devices without formal proof, where analogies to existing systems are close enough: consider the feasibility of making a clock from zirconium. The detailed design of many specific devices to render them describable by dynamical equations would be a task of another order (consider designing a clock from scratch) and appears unnecessary to the establishment of the feasibility of certain general capabilities.

    Protein design

    Biochemical systems exhibit a "microtechnology" quite different from ours: they are not built down from the macroscopic level but up from the atomic. Biochemical microtechnology provides a beachhead at the molecular level from which to develop new molecular systems by providing a variety of "tools" and "devices" to use and to copy. Building with these tools, themselves made to atomic specifications, we can begin on the far side of the barrier facing conventional microtechnology.

    What can be built with these tools? Gene synthesis (3) and recombinant DNA technology can direct the ribosomal machinery of bacteria to produce novel proteins, which can serve as components of larger molecular structures. One might think assembly of such components into complex systems would require a preexisting technology able to handle molecules and assemble them; fortunately, biochemistry demonstrates that intermolecular attraction between complementary surfaces can assemble complex structures from solution. For example, the complex machinery of the ribosome self-assembles from more than 50 different protein molecules and can do so in vitro (4).

    At present, the design of protein systems as complex as a ribosome seems an awesome task. Indeed, chemists cannot yet predict the three-dimensional conformation of a natural protein from its amino acid sequence, an ability