Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Reexamination Certificate
2000-12-15
2004-08-10
Brusca, John (Department: 1631)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
C435S006120, C435S069100, C530S350000, C536S024100
Reexamination Certificate
active
06774222
ABSTRACT:
STATEMENT AS TO RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSORED RESEARCH AND DEVELOPMENT
[Not Applicable]
FIELD OF THE INVENTION
This invention relates to novel molecular constructs that act as various logic elements, i.e., gates and flip-flops. The constructs are useful in a wide variety of contexts including, but not limited to, computation and control systems.
BACKGROUND OF THE INVENTION
The history of computational devices reveals a progression from larger and slower to smaller and faster devices. Huge stepwise advances in this progression have accompanied significant changes in the underlying technology. Thus, for example, vast increases in computational speed accompanied the transition from mechanical, hand-operated devices such as the abacus and hand operated cash-register or calculator to electrically driven mechanical computers (e.g., the electric cash register/calculator). Similarly significant increases in speed and decreases in size accompanied the shift from mechanical based devices to tube-based electronic computers, again with the shift from tube-based electronic computers to transistor-based electronic computers, and yet again with the shift from discrete transistor circuits to integrated circuits to large scale integrated (LSI) circuits.
The continually decreasing size and increasing speed of large scale integrated electronic devices has recently provoked increased interest and concern regarding the theoretical and practical limits of this progression. Such theoretical limits are affected by the inherent noise in electronic systems, the need to dissipate heat across ever decreasing surface areas as the feature size of various elements decreases, and the “anomalous” behavior of devices as their physical size decreases to a point at which quantum mechanical rather than macroscopic properties predominate. (It will be noted however, that the emergence of quantum mechanical properties at small feature size may provide the basis for quantum computing devices and this field is receiving considerable interest). Practical limits are imposed by costs and difficulties in predictable and reliable microfabrication.
Another approach to the improvement in computational power and/or efficiency has involved the substitution of “linear” computing systems in which a single processor sequentially performs the necessary operations in a calculation with “parallel” computing system in which components of each calculation are distributed across two or more processing elements. Parallel computing systems can achieve vast savings in computational time. For example, an algorithm running on 100 computing elements in parallel in principle can run about 100 times faster than the same algorithm on a single element that must process each operation sequentially. Of course the actual gain in efficiency is less than 100 because some time is lost in parsing the algorithm between the various computing elements, in integrating the elements, and because some elements may have to wait for other elements to complete their calculation before the next operation can proceed. Nevertheless, massively parallel systems have been able to solve problems (e.g., identify large prime numbers) that could not be practically determined on linear computer systems.
A combination of the two approaches, massive parallelism combined with small computational element size has birthed the field of molecular computing. This is illustrated in the seminal paper by Adleman (1994)
Science
266: 1021-1024, in which molecular biological tools were used to solve an instance of the directed Hamiltonian path problem. In particular, Adleman encoded the problem (a directed Graph) into nucleic acid sequences and then performed a series of ligations that ultimately produced an encoded solution which could then be decoded. Following Schneider (1991)
J. Theoret. Biol
., 148: 125, Adleman suggested that such molecular systems could demonstrate remarkable energy efficiency with a theoretical maximum of 34×10
19
operations per Joule while conventional supercomputers execute at most 10
9
operations per joule.
Adleman recognized that DNA molecular computing imposed certain difficulty and limitations, particularly on the encoding of various problems and recognized that conventional electronic computers have an advantage in the variety of operations they provide and the flexibility with which these operations can be applied. He did, however, note that for certain intrinsically complex problems, such as the directed Hamiltonian path problem where existing electronic computers are very inefficient and where massively parallel searches can be organized to take advantages of the operations provided by molecular biology, such molecular computations may be advantageous.
As indicated by Adleman, one limitation of prior molecular computation systems has been the lack of a variety of operations and the flexibility with which they may be applied.
SUMMARY OF THE INVENTION
This invention overcomes a number of these limitations by providing molecular logic devices that operate in a manner analogous to their electronic counterparts and thus provide a wide variety of operations. Thus, in one embodiment, this invention provides molecular bistable elements (flip-flops) and a wide variety of logic elements (gates) such as the AND, OR, NAND, NOR, NOT gates and others.
The central operational element of these devices is a nucleic acid having two or more protein binding sites (e.g., a first protein binding site and a second protein binding site). The sites are arranged such that when the first protein binding site is specifically bound by a protein, the second binding site cannot be bound by a protein that otherwise specifically recognizes and binds the second binding site; and when the second binding site is specifically bound by a protein, the first binding site cannot be bound by a protein that otherwise specifically recognizes and binds the first binding site. The binding sites are thus mutually exclusive. The nucleic acid can be a single or double stranded nucleic acid, however double stranded nucleic acids (e.g., DNA) are preferred. The first and the second binding sites can have the same or different nucleotide sequences. In one preferred embodiment the first and second binding sites are the same and have the nucleotide sequence of SEQ ID NO: 1 described herein.
The binding sites can be chosen so that they are specifically recognized (bound) by any of the nucleic acid binding proteins described herein (e.g., Fis, modified EF-tu, Tus, and LexA).
As indicated above, the binding sites are spaced so that they are mutually exclusive (only one can be bound at a time). The first binding site is preferably within 20 nucleotides (base pairs) of the second site, more preferably within 15 base pairs, and most preferably within 11 or fewer base pairs of the second site. Preferred binding sites have a strength of at least 2.4 bits as determined by individual information theory. The difference in strength between the two sites is at least 0 bits as determined by individual information theory.
The “flip-flop” may additionally include one or more selector binding sites (e.g. a third protein binding site) where the selector binding site is in proximity to the first protein binding site or to the second protein binding site such that specific binding of the third binding site (e.g., with a protein) precludes specific protein binding of the first or second protein binding sites.
In one preferred embodiment the flip-flop comprises the above-described nucleic acid in which the first protein binding site is a Fis binding site; the second protein binding site is a Fis binding site; and the binding sites are separated from each other by less a than 12 nucleotide base pairs. In a particularly preferred flip-flop the nucleic acid is a deoxyribonucleic acid comprising the sequence of SEQ ID NO: 2 or SEQ ID NO: 3 described herein.
In another embodiment this invention provides the various logic gates (NOR, OR, NOT, AND, NAND) described herein. The fundamental uni
Hengen Paul N.
Schneider Thomas
Brusca John
The United States of America as represented by the Department of
Townsend and Townsend / and Crew LLP
Zhou Shubo (Joe)
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