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1. One can think of the book problem, loosely speaking, in terms of the initial state and
final state of a thermodynamic system. When removing the book from the shelf, the
initial state of the book has but one “conformation” or “spatial orientation,” that of it
standing wedged between other books on a shelf in an orderly array. Following
removal, however, many orientations of the book are possible, even if it remains
closed. This increased number of “degrees of freedom” of the book has a higher
entropy than the “properly-shelved” state. Increases in entropy occur spontaneously
and are therefore thermodynamically favorable. Concerning spontaneity, we should
consider it much more probable for a book to lose its place on an orderly shelf and
become “randomly” orientated than for a book to move from a disorganized state to
an orderly one. There is clearly a connection between “spontaneity” and “ease.”
2. There are two bulbs, or chambers, so in rough terms any one molecule can occupy
either the left one or the right one. That is, in a manner of speaking there are two
accessible states to each molecule. So the total number of accessible states is 2 × 2 ×
2 …, the number of factors of two being identical to the number of molecules. If N
molecules are present, the number of indistinguishable states is 2N.
Ω = N!/(L!(N–L)!)
In the most probable state, the number of molecules in each bulb is the same, so
P = N!/((N/2)!(N/2)!2N)
It is interesting to examine the effect of the total number of particles on the likelihood
of a slight shift in the balance of concentration (± 1 molecule).
When N = 10:
ΩN–2±1 = 1000!/(501!499!)
ln(ΩN–2±1) = (1000ln1000 – 1000) – (501ln501 – 501) – (499ln499 – 499)
= 693.1
A standard calculator can’t handle this calculation when N~1023. The odds of a
difference in concentration under such conditions, however, can be determined. It is
found that this probability (1 – P) is smaller than 1/10400.
Ω = N!/(n1! n2! n3!…). Since 0! = 1 and 1! = 1, we can simplify our lives and ignore
all the empty and singly occupied “bins” in the configuration. This gives
Ωa = 20!/(19!1!) = 20
Ωb = 20!/(18!1!1!) = 20 × 19 = 380
Ωc = 20!/(17!1!1!1!) = 20 × 19 × 18 = 6,840
Ωc = 20!/(16!2!1!1!) = 20 × 19 × 18 × 17 / 2 = 58,140
and so on.
(N.B.: The subscripts are merely a convenient means of distinguishing one calculation
of Ω from another.)
In view of this,
This huge number is comparable to the age of the universe in seconds. Note that,
even if there are more than twenty “bins,” this has no impact on the magnitude of Ω
because 0! = 1.
5. “To be or not to be, that is the question.” There are 41 characters in this sentence,
including punctuation. Each of the 107 chimp typists has a 46-key keyboard (45 keys
plus one space bar). We are ignoring the shift key to keep things straightforward. We
will also assume that each key has the same probability of being depressed. This is of
course an oversimplification, because on most keyboards the space bar is the largest
key of all. This is relevant to typing monkey problems because realistically the
probability of a particular key being hit should be proportional to its surface area.
Now, the probability that the ‘t’ key or the ‘u’ key or the space bar will be “punched”
is 1/46, since there are 46 keys in total and we assume that each attempt to punch a
key is successful. The key to calculating how long it would take one chimp to type
the correct phrase is to realize that the probability of one key punch is completely
independent of the probability of another one. That is, the probability that an ‘o’ will
be typed on the second stroke does not depend at all on whether a ‘t’ is typed on the
first stroke. Thus, the probability that the correct sentence is typed is
How long it would take to do this, on the average? Assuming that each stroke takes
one second, it would take 1/P s to type every possible combination of letters 41
characters long in immediate succession and without duplication. This amount of
time is
This is not a long time but a very, very long time – longer than the apparent age of the
universe. However, what we want to know is the average amount of time required.
In some cases, the chimp will get things right relatively quickly, but not always. So
how long will it take on the average? One might not think so, but it will take about
the same amount of time as typing every possible combination of letters 41 characters
long in immediate succession and without duplication. To see how, we need the
formula
∞
Avg. time = L ∑ n * ((1 − p) n −1 p) = L{1(1–p)p + 2(1–p)2p + …} = L/p
n =1
where L is the length of the phrase (41 characters in this case), p is the probability of
getting the right phrase right, and p = (1 / c) L , where c is the number of characters
available (46 in this case). The formula comes from considering each set of 41
characters as a Bernoulli trial. The probability that the chimp will get it right the first
time is (1/46)41, and the time required for this is 41 s. The probability of getting the
phrase right during the second 41 s interval is the probability of getting right during
the first interval times the probability of getting it right at all. This is (1–
(1/46)41)(1/46)41, and the time taken is 82 s. In the next interval, the probability is (1–
(1/46)41)2(1/46)41, the time taken 123 s. And so on. The average time is 41/(1/46)41 =
6.1 × 1069 s. As we can see, this is about a factor of 4 larger than the time required to
type every possible combination of letters 41 characters long in immediate succession
and without duplication.
Now let’s let our chimp use a computer program to shift to the next character when it
gets one right. How much time will be required to produce the required sentence?
The time needed to get one character right will be
t = 1 / (2P) s = 1 / (2 × 1/46) s = 23 s
This must be done 41 times in all, so the total amount of time needed is just
t = 23 s for the 1st character + 23 s for the 2nd character + 23 s for the 3rd one + …
= 23 s / character × 41 characters
= 943 s = 15.7 min
If everyone spent 15.7 min per month reading Shakespeare, the world would be a
great deal more literate and humane than it is today. Well, be that as it may, the point
is that 15.7 min is much shorter than 1069 s! In the present case, although the
probability of getting the correct key did not change from one character to the next,
the probabilities were additive instead of multiplicative.
How does this inform our thinking on the origin of life and the development of
culture? Could it be that a “computer program” was “operating” silently on
molecular evolution during the early history of Earth? But this presupposes the
existence of “intelligence” many years ago and, moreover, its interaction with events
LONDON (May 9) - Give an infinite number of monkeys an infinite number of typewriters, the theory
goes, and they will eventually produce the works of Shakespeare.
Give six monkeys one computer for a month, and they will make a mess.
Researchers at Plymouth University in England reported this week that primates left alone with a
computer attacked the machine and failed to produce a single word.
In a project intended more as performance art than scientific experiment, faculty and students in the
university's media program left a computer in the monkey enclosure at Paignton Zoo in southwest
England, home to six Sulawesi crested macaques.
At first, said Phillips, ``the lead male got a stone and started bashing the hell out of it.
``Another thing they were interested in was in defecating and urinating all over the keyboard,'' added
Phillips, who runs the university's Institute of Digital Arts and Technologies.
Eventually, monkeys Elmo, Gum, Heather, Holly, Mistletoe and Rowan produced five pages of text,
composed primarily of the letter S. Later, the letters A, J, L and M crept in.
The notion that monkeys typing at random will eventually produce literature is often attributed to
Thomas Huxley, a 19th-century scientist who supported Charles Darwin's theories of evolution.
Mathematicians have also used it to illustrate concepts of chance.
The Plymouth experiment was funded by England's Arts Council and part of the Vivaria Project, which
plans to install computers in zoos across Europe to study differences between animal and artificial life.
Phillips said the results showed that monkeys ``are not random generators. They're more complex than
that.
``They were quite interested in the screen, and they saw that when they typed a letter, something
happened. There was a level of intention there.''
We can answer the question by thinking about the situation in terms of ITC. This
technique is often used to make repeated injections of a small volume of a ligand
solution into a larger volume of a macromolecule solution. Proper data analysis
involves taking several things into account: the change in ligand concentration (it
becomes more concentrated with each injection), the change in macromolecule
concentration (it is diluted on each injection), the change in total volume (the total
volume increases on each injection), and so on. One must also assume that thermal
equilibrium is attained relatively quickly after an injection, and there are ways of
being pretty sure of this. But does all this mean that the system is a closed one? No!
In actuality, the system is not closed, but immediately after an injection (which lasts
but a few seconds), there is no further change in the material contents of the reaction
cell, and the system is closed. The data from one injection to another can be
compared because adjusting the numerical values of results for small changes in
protein concentration, ligand concentration, and so on is assumed to be identical to
making appropriate small changes in the actual experimental situation. In other
words, one assumes that the result of an experiment in which the concentrations were
adjusted in actuality as required is identical to the result of taking such changes into
account mathematically. In some ways this is a very subtle point, and it places great
faith in the use of mathematics to describe the world we live in.
A suitable protocol could be developed from comments made above, and this should
be done as an exercise.
The gel gives the urea concentration at which half the molecules are unfolded. At this
concentration the free energy difference between the folded and unfolded states is 0.
From this one can determine the m value for unfolding, extrapolate to [urea] = 0, and
calculate the free energy difference between the folded and unfolded states when no
urea is present.
This approach probably would not give very accurate results in practice. Some
reasons for this are that polyacrylamide gels can change shape significantly on
staining and destaining, it might be difficult to tell whether the transition is essentially
© 2001-2007 by D.T. Haynie. All rights reserved.
a two-state transition, it might be hard to identify the point at which half of the
molecules are unfolded (assuming a two-state transition), the urea concentration
might vary uniformly along the abscissa, and so on.
where the superscript indicates the absence of denaturant. N.B.: the form of the
partition function depends on the model used to described the interaction of
denaturant with macromolecule.
11. One must remember that a sample in a scanning calorimetry experiment consists of a
suitable amount of purified macromolecule (protein) dissolved in buffer. One is
working with a collection of a large number of tiny particles, not one large particle.
Normalization for protein concentration puts thermodynamics measurements on a per
mole basis. In doing this, however, one must assume that the average behavior of the
ensemble of molecules represents the average behavior of one molecule over a
sufficiently long period of time.
The curve is not “infinitely” sharp. In the context of the ensemble, this tells us that
some molecules are unfolded at the beginning of the transition, half are unfolded
midway through, and the vast majority are unfolded by the end of the transition. With
regard to a single protein, however, the result tells us something subtly different: the
probability that any particular protein molecule will be folded or unfolded at a given
temperature.
There is another point we can make here. The melting of a pure solid occurs over a
narrow range of temperatures depends in part on long-range order. The order in a
solution of purified macromolecule is not very long-range, as it does not extend far
beyond the surface of the folded protein molecules, which are themselves aperiodic
on some level and of non-uniform rigidity.
13. Is the speed of the cyclist irrelevant to the number of times it must wash its cycling
gear because of splatted bugs? Consider walking in the rain. Have you ever noticed
that the faster you walk to avoid getting wet, the wetter the front of your shirt or
jacket becomes? This has to do with the relative motion of your body and the water
droplets. If the absence of wind, rain falls approximately vertically, so all droplets
will strike the top of your head – but only if you’re not moving. If you are moving,
then in a frame of reference at which you are rest, the droplets come at you at an
angle. This angle depends on the vertical speed of the droplets relative to the
motionless ground and your horizontal speed relative to the motionless ground.
If what we’ve said so far doesn’t make much sense, you will be delighted to know
that the situation with the bugs is different! Why? Because we have assumed that the
bugs move at random. The number of bugs you will encounter cycling will therefore
not depend at all on how fast you are going, only on the density of bugs in some
region of space and how far one travels through it. Whether a collision will result in a
stunned bug or perhaps a splatted one, however, will certainly depend on the rate of
cycling.
15. The dullard’s approach to this exercise is to list every possible tetrapeptide and then
count them:
AAAA
AAAC
AACA
ACAA
AAAD
AADA
ADAA
Etc.
If you had tried to write out each one of these, and writing and counting took 2 s per
peptide, the total time spent would have been 320,000 s = 3.7 days!
To answer the next question, we need to make some assumptions about what is being
asked for. Let’s suppose that we want to know the number of possible combinations
of amino acids in a tetramer if we start with exactly twenty different amino acids and
don’t add any as they get joined up. The number of possibilities at the C-terminus of
the peptide is 20, as before. The number of possibilities at the second one, however,
is just 19, since one has been removed. So
Now we want to think about composition and exclude all redundancies. This takes
into account, say, that AAAC, AACA, ACAA, and CAAA all have the same
composition, even though they are different chemicals. The calculation is as follows:
= number with one type of residue + number with two types of residue
+ number with three types of residue + number with four types of residue
= [20! / (19! 1!)]×1 + [20! / (18! 2!)]×3 + [20! / (17! 3!)]×3 + [20! / (16! 4!)]×1
= 8,855
This number is a lot smaller than 116,280. With regard to computing [20! / (18! 2!)]
× 3, consider choosing residues A and C. How many unique composition tetramers
are there? Just three: AAAC, AACC, and ACCC. How many different ways are
there to choose these two residues in the first place? 20!/(2! 18!) = 20 × 19 / 2 =
(number of possibilities for first residue) × (number of possibilities for second
residue, which must be different from the first one) / (number ways of ordering these
© 2001-2007 by D.T. Haynie. All rights reserved.
residues, since order does not matter when one is interested in composition and not
chemical structure). Note that the coefficients of the terms in the calculation of the
number of unique compositions of tetramer are from line four of Pascal’s triangle.
There is another, less elegant way of getting the right answer here, and that is to write
a little program to calculate the number of unique composition tetramers for you.
Here is just such a program to do that. It is, however, written for seven possible
amino acids instead of twenty. The reason for this is that is the fourth power of the
seventh prime number is more than a double precision variable can handle in
QBASIC, and QBASIC just happened to be the language available on my PC at the
time of writing (Jan. 2001). There are of course ways around this limitation, for
instance calculating x = log(a(1)) + log(a(2)) + log(a(3)) + log(a(4)), which gives a
number sufficiently small when a(1), a(2), a(3), and a(4) are as large as possible in
this exercise (71 in each case), but there’s another difficulty: when there are 20 amino
acid types the array b needs to be larger than the upper limit for a double precision
one-dimensional array in the version of QBASIC running on my PC. There are ways
around that, too, but my book is about biological thermodynamics, not techniques in
computer science! I won’t even feel bad if you can see a simpler way of writing the
code! The basis for the computation is a one-to-correspondence between amino acid
type and a prime number: A = 1, C = 2, D = 3… Y = 71. This approach is similar to
the one Kurt Gödel used to prove one of his famous incompleteness theorems. A
tetramer will have a unique composition if the product of the four primes representing
the amino acids is unique.
COMMON x AS DOUBLE
'Clear the screen.
CLS
'This array holds the first several primes.
DIM a(1 TO 7) AS INTEGER
a(1) = 1
a(2) = 2
a(3) = 3
a(4) = 5
a(5) = 7
a(6) = 11
a(7) = 13
'Don’t make the array too big.
DIM b(1 TO 250) AS DOUBLE
'Set all elements to a convenient value.
FOR z = 1 TO 250
b(z) = 0
NEXT z
'Loop for first amino acid.
FOR i = 1 TO 7
'Print the index. This says the program’s working.
PRINT "i ="; i
'Loop for second amino acid.
FOR j = 1 TO 7
'Print the index just to know what’s happening.
PRINT "j ="; j
'Loop for third amino acid.
FOR k = 1 TO 7
'This index is to move through array b.
m = 1
The triangle has many interesting properties from the point of view of number theory.
For instance,
row properties
1 All odd
2 All odd, symmetrical
3 Alternating odd and even, symmetrical,
center value is even
4 All odd, symmetrical, identical pair of odds
in middle
5 All even except at termini, symmetrical,
center value is even
6 Alternating odd and even, symmetrical,
identical of evens pair middle
7 Alternating odd and even, symmetrical,
center value is even
8 All odd, symmetrical, identical pair of odds
in middle
Note how certain properties are periodic. Can you think of other ways of appreciating
the structure of Pascal’s triangle?
17. We have a two domain protein with a ligand binding site in one of the domains. To
simplify things let’s assume that unfolding of the domains is cooperative. Now,
ignoring binding for the moment, the number of states is four: both domains folded,
one domain folded, the other domain folded, and both domains unfolded. It does not
matter here which of the domain binds the ligand. As far as ligand binding is
concerned, there is the unbound state and the bound state, and we assume that binding
does not occur in the unfolded state. Altogether, then, there are six states, since the
ligand can bind to two of the four species already described.
18. There are many possible ways of assessing the effect of including additional fitting
parameters in a model, and if you have any experience with curve fitting you may
well be familiar with several standard ones. As described in the text, an increase in
the number of parameters will ordinarily improve the apparent goodness of fit. So
why not include as many parameters as possible? One should be able to provide a
good argument as to why each parameter should be included. Quality of fit is often
measured by the sum of the squared residuals (SSR), the sum over all data points of
the square of the actual data point minus the fitted value. As we have said, the SSR
will usually decrease in value one addition of a fitting parameter (it might not
decrease if one tries fitting the data with a qualitatively different model). So a test of
the validity of including an additional parameter should take into account something
along the lines of the percentage change in SSR, or the ratio of the SSR to the number
20. The staggered conformation is much more probable than the one in which the methyl
groups form a mirror-image pair. There are therefore three possible orientations of
one methyl group relative to the other. These conformations are indistinguishable,
since all three hydrogen atoms or the methyl group are bonded to the carbon in the
same way. S = klnΩ = kln3. Note, though, that this calculation does not take into
account other relevant contributions to the entropy of a molecule, e.g. bond stretching
and translation of the center of mass of the molecule.
where the subscript indicating that the transition is from the folded state to the
unfolded state has been omitted from the thermodynamic functions for the sake of
simplicity.
Q = 1 + K = 1 + exp(–∆G/RT)
PF = 1/Q
PU = 1 – PF = exp(–∆G/RT)/Q