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Foresight Update 3 (page 4)

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Table of Contents - Foresight Update 3

Protein Engineering Survey

by James B. Lewis

Editor's note: Dr. Lewis, a Senior Scientist at the genetic engineering firm Oncogen in Seattle, has prepared a survey of the protein engineering and related fields from a nanotechnology perspective. Excerpts follow:

A protein engineering meeting entitled "Protein domains: molecular insights into structure/function relationships" was held at the Waksman Institute at Rutgers on Nov. 2-3, 1987. It was cosponsored by the newly created Center for Advanced Biotechnology and Medicine. The twelve talks brought together topics ranging from pure structure determination to molecular genetics.

A recently developed alternative approach to protein structure determination was introduced by Prof. Kurt Wuthrich of Switzerland. He explained how new techniques in nuclear magnetic resonance spectroscopy enable the determination of three-dimensional protein structures in solution so that it is not necessary to obtain a crystal to know the structure. In addition, you can directly compare how relevant the crystal structure is to the structure in solution. The results he presented were impressive. The limitations of the technique at the moment are (1) you can only do medium-size proteins, up to 25,000 daltons (about 230 amino acid units), (2) you need a 500 MHz machine, which costs over $500,000, and (3) you need several days of CPU time on a Cray supercomputer. The significance to nanotechnology of [this approach] is that our knowledge of the rules governing the relationship between protein sequence and protein structure, and between structure and function, is limited by the number of structures that we know. At the moment, this number is less than 200, but [new] techniques promise a rapid increase in this number.

[The current list of known protein structures is available in the Brookhaven Protein Data Bank.]

A novel, and controversial, presentation on protein evolution by Prof. Russell Doolittle of UCSD is directly relevant to the question of how many basic protein structures have been invented by nature. If this number is very large, then we have a long way to go to understand the structure/function motifs that nature has invented, and to figure out what novel motifs nature missed that we might use. Doolittle's work is not concerned directly with three-dimensional structure, but instead with the comparison of protein sequence information (about 30 times as many sequences as 3-D structures are known). He has shown that a surprisingly large number of these sequences are evolutionarily related, implying that most proteins are derived from a small number of basic themes. Recognizing that our current databases contain proteins chosen because someone wanted to work on them, rather than because an attempt was made to be representative, Doolittle estimates that there are fewer than a hundred fundamentally different protein structures in nature, including the ones that have not yet been described. If he is right, a solid understanding of sequence/structure/function relationships may not be too far off. The question then becomes: is this small number all that you can do with proteins; that is, did nature only make this many because the zillions of other possibilities are redundant or useless--or did nature just get lazy when she came up with a small number that worked so that these became "locked in" by evolution, while other good possibilities were ignored? Correspondingly, can we design additional structures that will have novel and useful properties, rather than being more minor variations on a well-studied theme?

Another meeting, "Protein Engineering '87", held at Oxford, was reviewed by M. Gait, J. Thornton, and R. Wetzel in Protein Engineering 1:267-270. The major topics appear to have been the usual attempts to use site-directed mutagenesis to improve commercially important enzymes. These experiments may be a bit dull compared to the ultimate use of protein engineering to develop nanotechnology, but we should remember that they are important for two reasons: (1) they help develop the knowledge of structure/function relationships that we need to design protein assemblers, and (2) they have immediate commercial applications, which will provide the near-term market force to drive nanotechnology development. Other topics included new algorithms for predicting structures from sequences. This effort is a bit academic from the nanotechnology perspective; however, there was also discussion of a new algorithm to do the reverse: predict a sequence that should produce a desired structure. Now this is something to follow! It is expected to be easier to do than predicting structure from sequence, and will be the heart of designing assemblers.

[One paper on the Web reporting an algorithm for reverse protein folding]

Table of Contents - Foresight Update 3

Other relevant technologies

Although the paper "The design of a biochip: a self-assembling molecular-scale memory device," by B.H. Robinson and N.C. Seeman (Protein Engineering 1:295-300) was published in a journal about protein engineering, it actually has nothing to do with proteins. It describes the design of a computer to be constructed using DNA, organic polymers, and metal ions. If the construction of such a computer were actually realized, it could utilize a readable bit of 3x104 nm3 , and would operate at electronic speeds over short distances. A novel feature of the design is the use of DNA for its structural--rather than informational--content. Oligonucleotides would be synthesized with sequences designed to give a particular pattern of complementarity so that they could be ligated together and would self-assemble into "nucleic acid junctions," a stiff scaffolding of DNA to be used to hold the working parts of the circuits into place. Molecular architecture and computer graphics programs to design these scaffolds are apparently available, and some experimental work has been done. The computer would use conducting organic polymers, such as trans-polyacetylene (tPA), in the preliminary design. The use of bundles of ten to twenty tPA "wires" is contemplated to ensure that the electronic properties are characteristic of bulk material. The problem of how to attach tPA to DNA has not been solved, but plausible solutions are presented. Metal ions chelated between adjacent tPA ends would serve as redox bits that could be manipulated by a connected voltage source through use of a suitable dopant in the polymer. A major feature is that the conductance would be electronic rather than through phonon-limited nuclear motion, so that speeds would be fast. The article explores several problems involved, along with suggested solutions, and an estimate of a decade for development. Although molecular in scale, the individual parts would be considerably larger than those of Drexler's suggested mechanical nanocomputer--but they might be faster, with estimated access times of picoseconds. Even with a relatively large bit size (by molecular standards), a cubic cm array would hold 3.3x1016 bits, or several hundred times as much as would be needed to store each of the estimated ten million books in existence.

[The 1989 NanoCon Conference featured talks on this topic by Ned Seeman and by Bruce Robinson, and an additional paper by Ned Seeman. In 1995, Ned Seeman was awarded the Feynman Prize for Nanotechnology.]

Table of Contents - Foresight Update 3

The "third path"

Current thinking (Update 1, p. 5) recognizes three technological pathways to nanotechnology: (1) protein engineering, (2) atomic manipulation through use of the scanning tunneling microscope (STM) and related technologies, and (3) other approaches to chemical synthesis... The third path was briefly considered in our previous installment by way of noting a short article in Science News that reported novel "Cages, Cavities, and Clefts" produced by organic chemists that are capable of recognizing atoms and small molecules. Although these developments are currently seen in terms of bulk-scale technology, they embody the principles of designing specific molecular recognition, until now exclusive to the realm of biology. These capabilities will surely become useful in designing molecular-scale machines for manipulating individual atoms. This area of research has been recognized by the 1987 Nobel Prize in Chemistry, showing once again that science at large is realizing the enormous potential of recognition and manipulation at the atomic scale. A short summary of the award-winning research, entitled "Chemistry in the image of biology" appeared in Science (238:611-612). It briefly describes how the work of the three Nobel laureates mimics enzyme systems in function by the creation of small organic "host molecules," typically one-tenth the size of enzymes, that will recognize "guest molecules," such as metal ions, and bind them to specially designed cavities, clefts, or cages. This host-guest chemistry is essentially trying to understand in atomic detail the general principles of how molecules recognize and react to each other. This knowledge will be an essential aspect of nanotechnological manipulations. It will enable our assemblers to feel, recognize, pick up, and put in place the atoms with which our technological dreams will be built.

[One example of work on host-guest and supramolecular chemistry. Another example.]

Readers who would like full copies of Dr. Lewis's Protein Engineering Survey may obtain them through FI. Please include a donation of at least $1 to cover our costs.

Table of Contents - Foresight Update 3

Foresight thanks Dave Kilbridge for converting Update 3 to html for this web page.

From Foresight Update 3, originally published 30 April 1988.
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