J. Phys. Chem.
B 2008, 112, 5883-5886 5883
Autobiography of Attila Szabo
I was born on September 6, 1947, in Budapest, Hungary. My
father was a painter, and my mother was a seamstress. Although
neither of them went to high school, it was clear from the very
beginning that they wanted me to go to university. I was an
only child and therefore quite spoiled.
My interest in science was aroused by a distant cousin when
I was about seven. For reasons that are still unclear to me, he
once brought over a bunch of test tubes and flasks filled with
liquids of different vivid colors. In addition, he gave my father
a red and a white powder. When gently mixed together, rolled
in a piece of paper and then stepped on, it exploded violently
with a huge bang followed by a tremendous puff of white smoke.
This made a lasting impression on me.
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Since I was born in September, I started school a year older
than my friends. When the revolution began in October 1956,
I was in the third grade. My parents decided to leave, primarily
Downloaded via INST OF CHEMISTRY on July 28, 2023 at 13:45:03 (UTC).
to give me a better life. My father arranged to get a letter
directing him to paint a house near the Austrian border. We
got on a train that was filled with people carrying huge suitcases
and even Persian carpets. While I don’t know for sure, the
Russians probably decided to let all these people escape. If they
would have shot a few people on one of those trains, my parents
would have never left. Nevertheless, we escaped just like in
the movies. We paid some villagers to guide us across the border
in the middle of the night. There were even flares being shot
up around us (no doubt fired by the villagers to give us our
money’s worth), and we had to hit the ground every time.
After crossing the border, we were bussed to Vienna. We
now had to find a country that would take us. My father decided
to go somewhere warm. Painting is a seasonal occupation and
he wanted to work the whole year around. All Hungarians
wanted to go to the U.S., and consequently, there were huge
lines at the embassy. My father did not like to stand in line, so
the U.S. was out. He considered Australia, but something went
wrong. Argentina seemed like a good choice because they
promised us an apartment. Apparently, we came very close to
going there. When my father was picking up our plane tickets
at the embassy, he overheard two people behind the counter
rapidly speaking Spanish. My father said, “Oh, my God, I could
never learn this language.” So, Argentina was out.
By this time, the only country that would take us was Canada.
We were to go to Winnipeg which was far from the warm place
we had envisioned. Fortunately, we were put into a holding
camp near Montreal. After visiting the city, my father was
excited that there were no igloos, and we “escaped” from the
camp. This is how we ended up in Montreal in the summer of
1957. Although purely accidental, this turned out to be the ideal
choice. I never had to worry about Vietnam. I started school in
the fall. I spoke very little English. Because my father was
Catholic, I was sent to a public school run by religious brothers.
The principal took a look at me and decided that I was just the
right size for the fifth grade. So because I was a big kid, I
skipped a couple of grades. In addition, high school was only
11 grades at that time. So, all through my education, I was
younger than my fellow students, not because I was smart but
because I was fat.
When I was around 11, my mother bought some shoe polish
that came in a bottle shaped like a flask. This sparked something
in me, and I got my parents to buy me a chemistry set. I soon
10.1021/jp800825t This article not subject to U.S. Copyright. Published 2008 by the American Chemical Society
Published on Web 05/08/2008
got tired of the rather boring experiments (which were presum-
ably exciting compared with those one can do today). So, I
bamboozled my father to get me all sorts of dangerous chemicals
from our pharmacist. My only real discovery involved lighting
a mixture of alcohol and carbon tetrachloride. After breathing
the fumes, I felt that my lungs were about to collapse. Perhaps
I had found a way of making phosgene.
At this time, the major goal of my life was to discover the
nature of the two powders that my cousin had given us in
Hungary. The central problem facing any young chemist is that
it is difficult to get really big bangs. Nitrogen triiodide gives
only small pops. One day I was rubbing potassium chlorate
crystals against a matchbox to make sparks. I immediately
recognized the smell. The two chemicals must have been
potassium chlorate and red phosphorus. How could I get my
hands on a little red phosphorus? Who would sell some to a 14
year old boy? Well, Fisher Scientific would. I still remember
excitedly bicycling home with a large tin of red phosphorus. I
could now really impress my friends with ear-deafening
explosions followed by enormous puffs of white smoke. At
about this time, I started to become interested in theory and, in
particular, the nature of chemical bonding. I was soon trying to
read some college chemistry textbooks, learning about
s, p, d, ... , orbitals and all that. In the spring of 1963, I entered
a science fair with a project dealing with atomic structure.
I went to McGill in 1964 but continued living with my
parents. I took only math, physics, and chemistry classes after
my freshman year. The most significant thing I did as an
undergraduate was to convince Branka Ladanyi, who was in
many of my physics classes, to switch to chemical physics from
physics. In 1967, I started thinking about graduate schools and
wrote letters to several theoretical chemists including Robert
Parr and Martin Karplus. I was admitted to several places but
in the end chose Harvard probably because it was the only
school my mother had ever heard of. I arrived in Cambridge in
September 1968. In the beginning, Harvard was a little
intimidating. I had to take a p-chem entrance exam. One of the
questions asked for the eigenvalues of a harmonic oscillator
with an infinite reflecting wall down the middle. At first I didn’t
know how to solve it, and I remember saying to myself that
since I wanted to be a quantum mechanic I should be able to
do it and it can’t really be all that hard. Eventually, I did figure
it out and I was quite proud of myself. After the exam, I
overheard two organic chemistry students say, “Oh yeah, that
harmonic oscillator problem was really easy!”
I had decided to work with Martin. The first problem that he
suggested was to analyze NMR experiments on paramagnetic
iron-porphyrin complexes done by Kurt Wüthrich and Robert
Shulman. I had to learn about pseudocontact shifts, Kramers
doublets, g tensors, and all that. I worked on this for about a
year and my thesis has a long chapter on it, but we never
published anything. I did not find this problem too exciting and
never imagined I would ever do anything with NMR again.
In the spring of 1970, Martin suggested that we go to MIT
to hear a series of lectures by Max Perutz on how hemoglobin
works. After the lectures were over, Martin told me that the
time was right to think about making a model for hemoglobin.
5884 J. Phys. Chem. B, Vol. 112, No. 19, 2008
I seem to remember thinking why in the world would he want
me to make a ball and stick model of the structure of
hemoglobin! Fortunately, it soon became clear that what Martin
had in mind was a statistical mechanical model. He wanted me
to construct a model of Perutz’s mechanism that could be used
to quantatively understand the vast amount of experimental data
available in the literature. Coincidentally, the year before, I went
to a lecture by Harden McConnell where he gave the formulas
for the binding curves obtained by Linus Pauling for some
simple models of cooperativity. At the same time, I was taking
a course from Roy Gordon who just showed us how easy it is
to treat a lattice gas using the grand canonical partition function.
Just for fun, I rederived Pauling’s results using this technique.
So, a year later, I could really impress Martin by tackling the
problem using this elegant formalism. If it were not for this
happy coincidence, I am sure that using the grand partition
function would have never occurred to me.
I find it remarkable that my approach to science was so
different then. I simply had too much energy. I began by reading
Perutz’s two famous 1970 Nature papers countless times and
then proceeded to formulate the most faithful representation of
his ideas including all the bells and whistles. I considered both
oxygen and proton binding and several different kinds of “salt-
bridges”. Needless to say, the partition function was a sum of
many terms and looked pretty complicated. Then, one night, as
we were writing all this up, I started fooling around by
combining various terms. To my amazement, I soon discovered
that the entire partition function could be written in a simple
form that had the same structure as that of the Monod-
Wyman-Changeux allosteric model. So, in effect, what we did
was provide a microscopic, structural interpretation of their
phenomenological parameters. Had I started by formulating the
simplest possible model that captures the essence of Perutz’s
mechanism, I would have seen this immediately.
My experience in graduate school was truly wonderful. I
learned so much from so many people. At that time, all
theoretical grad students and postdocs had their offices in an
old detached home called Prince House. A remarkable number
of now well-known theorists were there at one time or another.
They worked on a wide variety of topics and were more than
willing to talk about their work to anyone who would listen. I
am a good listener. I do not wish to mention them all by name
because I am afraid I’ll leave someone out. So, I will focus on
two of my office mates who had the biggest influence on my
scientific life.
Neil Ostlund was Martin’s postdoc and a real quantum
chemist, being a student of John Pople. Since quantum chemistry
was my first love, I spent a lot of time talking to him and others
in Prince House who were applying many-body theory to
electronic structure problems. Neil showed me how one can
understand the relationship between different sophisticated
approaches by applying them to a simple minimal basis model
of the hydrogen molecule. A few years later, when he was at
Arkansas and I was in Indiana, we decided to write a small
book that would make complicated things look easy. We worked
on this with great enthusiasm all through the late 1970s, and
the scope of the book expanded. We each gave what was the
best in us, fighting over every word and equation. It was a true
collaboration. We are still very happy that we were crazy enough
to have written a book so early in our careers and that many
people seem to have actually learned something from it.
The other person was Klaus Schulten. He arrived in the fall
of 1969 and ended up working with both Roy Gordon and
Martin Karplus. We became good friends and saw many sunrises
together from our office window. His impact on my science
really started when in 1976 he and Zan Luthey-Schulten invited
me to spend the summer at the Max Planck Institute for
Biophysical Chemistry in Göttingen, but more about this later.
In the fall of 1971, I found out that Martin was planning to
go on sabbatical in Paris the next year. So, I modestly suggested
to him that if he would give me my Ph.D. after just four years
in grad school, I could go to France with him as a postdoc and
it would not cost him a penny. I was Canadian, and pretty sure
that I could get a fellowship from the National Research Council.
Happily, Martin went along with this and I arrived in Paris in
September 1972 to continue working with him on hemoglobin.
The next year, I went to Cambridge, England. Since I had my
own money, I had desks both in the Department of Theoretical
Chemistry with David Buckingham and at the Medical Research
Council Laboratory of Molecular Biology with Max Perutz. I
began worrying about trying to find a job. I thought I would go
back to Canada, but I ended up accepting an offer from Indiana,
where Peter Langhoff, a former Karplus postdoc, had a faculty
position.
I arrived in Bloomington in August 1974 and started to worry
about what kind of research to do. I will now try to describe in
some detail how I ended up working on different problems that
became life-long interests. Hopefully some readers who are just
starting their careers will find it interesting.
In the course of my work on using linear free energy relations
to try to understand hemoglobin kinetics, I wondered what the
maximum rate of ligand binding would be. Thus began my long-
term love affair with diffusion-controlled reactions. At first, I
worked on extending Smoluchowski’s calculation of the rate
constant to anisotropic (e.g., a small absorbing hole on the
surface of a protein) and fluctuating (e.g., the hole opens and
closes) reactivity. Then, one day I realized how little I
understood. On the molecular level, an irreversible bimolecular
reaction can occur only once. So, what does this have to do
with the steady-state flux to an absorbing surface that can
repeatedly kill particles? Although this puzzle was solved long
ago, the answer is still not widely appreciated. In any case, I
started to think about the many-particle aspects of irreversible
and then reversible bimolecular reactions. It turned out to be
challenging to develop a microscopic theory of the kinetics of
reversible diffusion-influenced reactions on all time scales. One
reason is that the relaxation to equilibrium does not follow an
exponential time course but rather a power law. I started working
on this in the late 1980s with Noam Agmon. It is only relatively
recently that Irina Gopich and I managed to formulate a general
theory that has a remarkably simple structure.
One day, I was talking to another assistant professor, Mark
Wightman, who was sticking microelectrodes into rat brains to
measure neurotransmitter levels. His electrodes were made by
embedding an ultrathin carbon fiber into a glass rod. It occurred
to me that the problem of calculating the current to such an
electrode is essentially the same as obtaining the flux through
a small hole in a protein. So, I actually knew something about
his problem without realizing it. Because one of my high school
science fair projects dealt with the electrolysis of water, I thought
it would be fun to do something in electrochemistry, and I ended
up writing about ten papers in this area.
In the summer of 1976, I went to visit Klaus and Zan Schulten
in Göttingen. I stayed in a guest house at the Institute, and since
I do not speak a word of German, all I could do was work (and
eat and drink). Klaus suggested that we work on something
completely different. One of his colleagues had started doing
experiments on exciplex formation of two optical probes

attached to the ends of a polymer, so Klaus proposed we work
out the theory. I had no idea how to start. I knew about Paul
Flory’s book on polymer chemistry but had only looked at
it, and it didn’t seem to discuss kinetics. As I later found
out, Marshall Fixman wrote a couple of important papers on
this subject around this time. If I had seen them, I would
have probably stopped immediately because they looked so
complicated. So, sometimes ignorance is not really such a bad
thing.
I began by making up the simplest possible model that I had
some chance of solving. Needless to say, it had to be one-
dimensional. My polymer was made up of unit vectors or bonds
that could independently point either left or right. Each bond
could flip with a certain rate. Amusingly, this model was the
same as the one Bob Zwanzig, Biman Bagchi, and I used many
years later to illustrate Levinthal’s “paradox” in protein folding.
The ends of this polymer touch when equal numbers of bonds
point left or right, and we wanted to know the mean time it
takes to reach this conformation.
It was easy to write down the set of discrete rate equations
for the end-to-end distance distribution because they are the
same as those that describe the kinetics of ligand binding to a
“super-hemoglobin” with N noninteracting sites. Late one night,
it occurred to me that one could make life simpler by taking
the continuum limit. In this way, I derived a partial differential
equation for the probability distribution of the end-to-end
distance. Although I was too ignorant to know at the time, it
turned out to be simply the Smoluchowski equation for diffusion
on a harmonic surface. All of this is so obvious to me now that
it is hard to believe how much I struggled then.
So, to find the distribution of lifetimes of our one-dimensional
polymer with reactive ends, we had to solve this equation subject
to an absorbing boundary condition at the minimum of the
potential. I immediately realized that this problem is almost
exactly the same as the one on my Harvard entrance exam that
I mentioned previously. Using the properties of Hermite
polynomials, I expressed the survival probability analytically
as an infinite series. At the same time, Klaus was also trying to
solve this problem. He was aware of the analytic expression
for the Green’s function of a diffusive oscillator and then used
the method of images to get an extremely simple expression
for the survival probability (the inverse sine of an exponential).
I am still jealous. We then looked up the Taylor series expansion
of the inverse-sine, and lo and behold, the two expressions were
identical. It’s fun to collaborate.
We generalized our model to three dimensions by describing
the stochastic dynamics of the polymer as diffusion under the
influence of the potential of mean force between the reactive
ends. This is the simplest model that describes relaxation to
the equilibrium distribution of end-to-end distances. Our excite-
ment soon faded because we could not make any progress in
analytically calculating the kinetics. On my next trip to
Göttingen, we tried again. One day, I was looking at a newly
arrived book in the library, called “Stochastic Models in
Biology”, by Goel and Richter-Dyn. It seemed pretty compli-
cated to me, but somehow, I managed to see that it contained
the answer to all our prayers. It showed that, if one is interested
only in the mean lifetime (which is the same as the mean first
passage time to an absorbing boundary), one can bypass the
solution of the time dependent diffusion equation and only solve
a simple inhomogeneous differential equation.
All the rest was easy, but it took us a couple of years to
actually write it up. Zan Schulten had developed an efficient
finite-difference algorithm for solving the Smoluckowski equa-
J. Phys. Chem. B, Vol. 112, No. 19, 2008 5885
tion which she used to test a single-exponential approximation
to the survival probability we proposed. In addition, she made
an important theoretical contribution to the paper. I generalized
the formalism to handle partially absorbing boundaries but I
used the free-diffusion form of the boundary condition even in
the presence of a potential. This seems manifestly wrong.
However, Zan was able to prove that in the context of first
passage times it was actually correct. So, it does not hurt to be
a little lucky sometimes. Our paper lay dormant for a long time.
It eventually did attract the interest of experimentalists, mostly
in the area of protein folding, which started when Bill Eaton
walked in my office one day and asked if I knew how the rate
of loop formation scaled with length.
In the 1970s, Indiana was a hotbed of NMR because of Adam
Allerhand, a pioneer in the use of wide-bore magnets and an
expert in 13C NMR relaxation. He got Frank Gurd, a biochemist,
interested in using NMR to study the dynamics of side chains
in myoglobin. Frank had a graduate student, Dick Wittebort,
who one day came to my office to ask me for help with some
papers he was trying to understand. I told him that I knew
nothing about NMR relaxation but I did know something about
spherical harmonics and Wigner rotation matrices because of
all the quantum mechanics courses I had taken. In this modest
way, we began a collaboration that had perhaps the greatest
impact on my scientific life. We learned lots of new things
together. Although I had heard of correlation functions before,
this was the time when I actually learned how to calculate them.
We then began to make existing models more realistic, for
example, by considering restricted rotational diffusion about
carbon-carbon bonds in amino acid side chains. Alternatively,
to treat excluded volume, we described side-chain dynamics as
jumps between discrete configurations on a diamond lattice. We
worked on this for a couple of years, and in 1978, we published
our first (and my most complicated) paper on NMR.
Then, Dick graduated and went to MIT as a postdoc. A new
graduate student from Italy, Giovanni Lipari, arrived and for
some reason, wanted to work with me. I suggested that he
continue where Dick left off and think about the dynamics of
DNA. At that time, I went to a seminar on fluorescence
depolarization of probes embedded in liquid crystals. This was
another topic I knew nothing about, but as I listened, it became
increasingly evident that the underlying theory was closely
related to that used to describe NMR. This probably was the
first time I ever heard the word “order parameter”. Trying to
understand fluorescence forced me to think in the time domain,
and this makes life easier than thinking in the frequency domain
(i.e., spectral densities and all that).
Giovanni found that he could analyze experimental data
equally well using a variety of physically different models of
internal dynamics. Moreover, the parameters of more complex
and hence more physically realistic models could not be
uniquely determined. This made us reexamine the underlying
theory, and it was soon clear that the measured relaxation
parameters simply do not depend on all the details of the internal
dynamics when the dynamics are sufficiently fast so as to be in
the so-called extreme narrowing limit. In this limit, the NMR
experiment cannot tell you if a bond is rotating about an axis
or wobbling in a cone when the corresponding order parameters
are the same. This is why we called our approach to the analysis
of NMR relaxation experiments “model-free”.
We knew all of this before coming to the NIH, but it took us
a couple of years to write it up because we wanted to do the
best job possible. Giovanni died in an accident before the proofs
arrived, a tragedy that absolutely devastated everyone who knew
5886 J. Phys. Chem. B, Vol. 112, No. 19, 2008
him. When he first came to Indiana, he told me that his mentor
in Italy advised him not to work with an unknown assistant
professor. In general, this is sound advice and something I can
see myself saying. Over the years, I have thought many times
that he should have taken it. He most probably would still be
alive if he had followed a different timeline.
I managed to work on NMR relaxation without ever learning
Redfield theory or even reading the relevant chapter in Abragam.
However, for some reason that escapes me now, I carefully
studied the section in Abragam on Anderson’s theory of line
shapes when the frequency fluctuates because of chemical
exchange. This was perhaps the most influential single thing I
ever read. It is pretty obvious that one can use the same
formalism (by making the frequency imaginary) to describe
irreversible unimolecular kinetics with fluctuating rates. It is
more surprising that it would end up playing a crucial role in
my recent work, not only with Irina Gopich on analyzing single-
molecule fluorescence experiments but also with Gerhard
Hummer on extracting free energy profiles from non-equilibrium
pulling experiments. Ultimately, the reason that all of these
physically different problems are mathematically so closely
related is that, in the absence of fluctuations, the magnetization
in NMR, the survival probability in kinetics, the generating
function for Poissonian photon statistics, and the Boltzmann
factor are all single exponentials.
In the fall of 1979, I came up for tenure. For a while, there
were all kinds of rumors why I did not get it. The reason was
simply that the chairman felt that, while I was a good scientist,
I was not the kind of person who would catapult the department
to the next level. This was not such an unreasonable assessment
at that time. I was a bit unfocused, working on NMR, atomic
physics, hemoglobin kinetics, and finishing a book on quantum
chemistry (an area in which I wrote only a handful of papers).
Although I never told my parents, I was never too upset about
all this, even though I tried to cause as much trouble as possible
by exhausting all appeals. I suppose I never really liked living
in a small town like Bloomington and thought that this was
just an opportunity to get away from there.
Not getting tenure at Indiana is a little bit different than not
getting tenure at Harvard. My options seemed rather limited
even though I just had my NIH grant renewed. Then, I got lucky.
Martin Karplus told Bill Eaton about my predicament and said
that I was smart. This was basically it. Bill created a job for
me, and I arrived at the NIH in December of 1980.
The NIH turned out to be the perfect place for me. I have
been given complete freedom to do whatever I want. I am
surrounded by great and highly interactive scientists. I do not
have to apply for grants, which I always hated because I never
know what I am going to do next. Since I do not have to teach
or write grants, I have plenty of time to be intimately involved
with all the details of the research I am doing. As you can see
from my bibliography, I had the privilege to work with many
people, both theorists and experimentalists. I would like to take
this opportunity to thank all of my collaborators for making
my scientific life both fun and reasonably productive.
I like to think that the Laboratory of Chemical Physics at the
NIH is the best biophysical chemistry lab in the world. It was
started in the 1940s by F. S. Brackett of hydrogen atom fame.
It was built up by Bill Eaton based on a simple idea: Hire the
best scientists you can, and do not worry too much about what
they are working on at the moment. It has been a great place to
work. The lab has some reasonably well-known NMR spec-
troscopists: Ad Bax, Marius Clore, and Rob Tycko. The first
two are among the top 20 most-cited chemists in the world.
Our higher-frequency spectroscopists are not too bad either: Phil
Anfinrud, Bill Eaton, Jim Hofrichter, and Ira Levin. Ira, who
pioneered two-dimensional infrared imaging, has been a major
force in maintaining the tradition of strong support for basic
science in our institute. Finally, there are the theoreticians
Gerhard Hummer, Eric Henry, Irina Gopich, Bob Zwanzig, and
our most recent addition, Artur Adib (Bob, who joined us in
the late 1980s, just retired but still comes to the Lab as a
Scientist Emeritus). I have learned a great deal from all of them.
I cannot imagine having nicer or more stimulating colleagues.
Although I have some good stories about the 27 years I spent
at the NIH, I have run out of steam. I realize that it is unusual
not to spend more time talking about the most important part
of one’s career, but in this way, I can at least avoid boring you
even further.
Attila Szabo