On the Scalability of Molecular Computational
Solutions to NP Problems
Dónall A. Mac Dónaill,
(Department of Chemistry & Centre for Scientific Computation,
Trinity College, University of Dublin, Ireland
dmcdonll@tcd.ie)
Abstract: A molecular computational procedure in which
manipulation of DNA strands may be harnessed to solve a classical
problem in NP  the directed Hamiltonian path problem  was recently
proposed [Adleman 1994], [Gifford 1994]. The procedure is in effect a
massively parallel chemical analog computer and has a computational
capacity corresponding to approximately CPU years on a typical 10
MFLOP workstation. In this paper limitations on the potential
scalability of molecular computation are considered. A simple analysis
of the time complexity function shows that the potential of molecular
systems to increase the size of generally solvable problems in NP is
fundamentally limited to . Over the chemically measurable picomolar to
molar concentration range the greatest practical increase in problem
size is limited to Key Words: Molecular Computation, DNA, NPproblem
1 Introduction
The (directed) Hamiltonian Path Problem (HPP), first proposed by
William Rowan Hamilton, is one of the most troublesome problems in
Graph theory. Very similar to the Euler path problem, it may be stated
as follows: for a graph G with vertices , and edges , is
there a path which starting and ending at specified vertices, visits
each remaining vertex once and only once? A trial and error approach is theoretically possible but proves
impossible in practice for all but the smallest graphs; the number of
paths which it is necessary to check simply grows too rapidly. In fact
the HPP problem belongs to a class of problems called NPcomplete,
which rapidly become too complex to be solved by standard
(deterministic) computers. Problems of this nature are of considerable importance in computer
science. There was therefore considerable interest in a recent report
by Adleman which suggested that modern laboratory techniques of
molecular biology could be employed to manipulate strands of DNA so as
to solve the HPP [Adleman 1994]. A subsequent study has suggested how
the method may be adapted for the solution of another classical
problem in NP  the "satisfiability" or SAT problem [Lipton 1995]. Page 87
Adleman's insight lay in exploiting the parallelism inherent in
chemical systems to yield a massively parallel analog computer, in a
brute force approach to solving complex problems in NP. However, while
it was noted that chemical systems  and thus molecular computers 
can be easily scaled in size, the fundamental question of the
scalability of problems solvable by molecular computation was left
open. This paper addresses this central issue and, because the
discussion draws on the diverse disciplines of molecular biology and
computer science, begins with a brief review of both problem
classification and Adleman's experiment.
1.1 Classification of Problem Complexity
Time complexity functions describe how the cost of solving a problem
grows on increasing the size (or input length), n, of the
problem. Computer scientists recognize two distinct classes [Garey and
Johnson 1979]. Algorithms for which the time complexity function is
O(p(n)), where p(n) is a polynomial in n, are termed polynomial time
algorithms, whereas algorithms with no polynomial bound on their
complexity are called exponential time algorithms. There is a
remarkable difference in growth rates between polynomial and
exponential algorithms [Fig. 1]. Figure 1: Time complexity functions for some polynomial (n, ) and
exponential () functions as a function of problem size, n. Page 88
Problems with polynomial algorithms are considered "good", whereas
problems which are so difficult that no polynomial time algorithm can
solve them are termed "intractable". The theory of NPcompleteness is concerned with decision problems.
Informally, a decision problem is said to belong to the class P if
there exists a Deterministic Turing Machine (DTM) program which solves
the problem in polynomial time. Nondeterministic computation differs
from deterministic computation in that a solution is exhaustively
guessed and then checked. If a correct solution to a decision problem
can be checked in polynomial time, then that problem is said to belong
to the class NP (Nondeterministic Polynomial time). Since problems
which can be solved deterministically in polynomial time can also be
guessed nondeterministically and checked in polynomial time, we can
write P NP [Fig. 2]. It is not known whether this inclusion is
proper, that is whether NP\P is occupied. A practical difficulty with problems in NP is that their
timecomplexity with a deterministic algorithm is exponential. Thus
problems in NP are intractable with deterministic machines. Certain problems in NP have the property that all other problems in NP
may be polynomially reduced to them, and are termed NPcomplete. If a
polynomial time algorithm can be found for any member of this
equivalence class then one can be found for all problems in NP. In
other words, if for any (problem) NPcomplete, then P if
and only if P = NP. Problems NPcomplete may be regarded as the
hardest problems in NP. The relationship between P, NP and NPcomplete
is illustrated below Figure 2: Classification of problem complexity
Not surprisingly the class of NPcomplete problems has been the focus
of considerable attention; including some recent ideas on "Quantum
Computers" [DiVincenzo 1995] which could in principle solve NP
problems in polynomial time. Several classical problems such as the
Hamiltonian Path problem, the satisfiability problem have been shown
to be NPcomplete. For a more complete Page 89
discussion of these points the reader is referred to the work of Garey
and Johnson [Garey and Johnson 1979].
1.2 Molecular Computation and the HPP
The following is a simple nondeterministic algorithm for solving the HPP
[Adleman 1994]:  (Step I) generate random paths in the graph
 (Step II) keep only those paths with begin and end at the specified
vertices.
 (Step III) for an n vertex graph keep only those paths with n vertices.
 (Step IV) keep only those paths which visit each vertex once.
 (Step V) if any paths remain then those paths are Hamiltonian and the
answer to the HPP is "Yes". Otherwise "No".
Adleman demonstrated, using a graph small enough to be solved by visual
inspection [Fig. 3], that DNA could be used to solve the Hamiltonian Path
Problem ( NPcomplete). Figure 3: The directed graph used by Adleman. For and the edges 01, 12, 23, 34, 45, 56, define a Hamiltonian path. 20mer oligonucleotides were associated with each vertex in the graph.
Oligonucleotides representing edges , linking vertices and , consisted
of the 3' 10mer of and the 5' 10mer of [Fig. 4]. The highly
specific binding of nucleotides A with T and C with G are such that
strands which are WatsonCrick complementary to , denoted ,
serve to link compatible edges [Fig. 4]. Thus, ligation reactions can
only generate nucleotide polymers corresponding to random paths on the
graph. Page 90
Step I is the most critical step in the algorithm as it is essential
that all paths be explored, a task with exponential time complexity on
a deterministic machine. Adleman addressed this by employing 50
picomole quantities of nucleotides corresponding to edges and the
WatsonCrick complement of vertices. While 50 picomole quantities are
minute in chemical terms, the parallelism of chemical systems is such
that they correspond to copies of each edge and vertex 
presumed sufficient to ensure that polymers corresponding to all paths
in the graph are generated.
Figure 4: (a) DNA strand corresponding to vertex . (b) WatsonCrick
complement of vertex . (c) strands corresponding to edges and .
Nucleotide specificity in binding (AT and CG) ensures that vertex serves to
bind edges and . The remaining steps (IIV) in the algorithm were executed using
standard laboratory techniques. Polymers corresponding to paths
between the specified starting vertex and finishing vertex were selected (Step II) and amplified (i.e. concentration increased)
by using the polymerase chain reaction (PCR). Argose gel
electrophoresis was used to identify those polymers corresponding to
paths involving n (= 7) vertices (Step III), and the product was again
amplified using the PCR. Step IV was implemented using affinity
purification for oligonucleotide sequences corresponding to vertices
1, 2, 3, 4, 5 and 6. Any remaining polymer must correspond to a
Hamiltonian path, and a suitably primed PCR was employed to detect and
amplify any such polymer.
2. Scalability of Molecular Computation
2.1 Computational Capacity of Molecular Computers
In Adleman's original paper the question of the scalability of
problems solvable by molecular computation was left open [Adleman
1994]. The system contained 14 edges, each represented by 50 picomoles
of nucleotide, corresponding to a total of 5 x edge
nucleotides. Associating each nucleotide binding with a computation,
Adleman's molecular system yielded a total of Page 91
computations. Concentrations could easily be scaled to yield
computations [Adleman 1994], which may be easily shown to correspond
to CPU years on a typical 10 MFLOP workstation. Given this phenomenal computational capacity, and the ease with which
chemical systems can be scaled, it would be easy for the
nonspecialist to conclude that the potential for molecular
computation is practically unlimited. This is not the case; [Lineal
and Lineal 1995], [Bunow 1995] and [Lipton 1995] have identified
problems in the potential scalability of Adleman's method. The
following analysis quantifies these limitations. Problems in NP, among them the directed Hamiltonian Path problem, have
a time complexity of , where n is the ''size`` of the problem and
p(n) a suitably defined polynomial in n [Garey and Johnson
1979]. Taking the best case situation, p(n) = n, the cost of solving a
problem of size using a given computational resource is . Increasing
the scale of the molecular system by a factor allows for the solution
of larger problems, the size of which, , is given by solving the
equality and the increase in the size of solvable problem, , is given by
The limitations expressed in equation (2) on the capacity of molecular
computers to solve problems in NP are forcefully illustrated by
considering limits on the scale of chemical systems. In practice,
electroanalytical techniques allow for the detection of chemicals in
the picomolar range [Dong and Wang 1988]. However, if we set aside
this technological limit, and assume that individual molecules can in
principle be detected (as in scanning tunnelling microscopy), then the
smallest possible molecular computers would consist of order unity
molecules. The largest conceivable molecular computer would involve all particles
in the universe. Of course, the amount of matter in the universe is
not known, but it may be reasonably estimated as follows: Taking
Hubbel's constant as [Kaufmann 1994] the age of the universe is 1.3
x years or 4.1 x seconds. Expanding at the speed of light this gives
the volume of the universe as 7.9 x . Further assuming a universe with
critical density, [Kaufmann 1994], i.e. a universe which has just
sufficient matter to be closed, the mass of the universe may be
estimated as 8.7 x . This is the equivalent of particles of mass 1
a.m.u. (taking Avogadro's number as 6.02 x ). Page 92
Assuming therefore for the purposes of illustration that the universe
contains particles, it follows that the size of molecular
systems can span a maximum 80 decades, and the greatest possible
increase in solvable problem size is given by equation (2) as Thus the potential to increase the size of problem (in NP) which may
be solved, by increasing the size of the chemical system, is very
modest indeed, even when fantastic scales are involved. More relevantly, over the realizable/detectable picomolar to molar
concentration range we have
Thus while the size of molecular computers can be readily increased,
the increase in the size of problems which such systems could solve is
much more modest. The scalability of problem size with the size of
molecular system employed is illustrated in Fig. 5. Page 93
Figure 5: Increase in solvable problem size with increase in the size
of the molecular computer (relative to the size of problem solvable
with a system of order unity molecules).
3 Conclusion
The potential of molecular systems to increase the size of solvable
problems in NP is fundamentally limited to the order of
. Nevertheless, the computational capacity of Adleman's approach is
enormous, equivalent to CPU years on a 10 MFLOP
workstation. The analysis is general and based on the time complexity
function, which gives the time in which a solution is guaranteed to be
found, and is therefore a worst possible case analysis; faster
solutions may be available in many cases. It is not therefore
suggested that there will be no instances where molecular computers
will prove superior to electronic computers.
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Acknowledgments The author would like to thank Dr. T. Tuohy (Department of Molecular
Genetics, Biochemistry and Microbiology, University of Cincinnati,
Ohio), Dr. J. Greer Page 94
(Department of Chemistry, Trinity College Dublin) and Dr. H. Gibbons
(Department of Computer Science, Trinity College Dublin), for useful
discussions. Page 95
