Perspective

AlphaFold – A Personal Perspective on

the Impact of Machine Learning

Alan R. Fersht

MRC Laboratory of Molecular Biology, Hills Road, Cambridge CB2 0QH, UK

https://doi.org/10.1016/j.jmb.2021.167088
Edited by Dr. Daniel Otzen

Abstract
I outline how over my career as a protein scientist Machine Learning has impacted my area of science and
one of my pastimes, chess, where there are some interesting parallels. In 1968, modelling of three-
dimensional structures was initiated based on a known structure as a template, the problem of the path-
way of protein folding was posed and bets were taken in the emerging field of Machine Learning on
whether computers could outplay humans at chess. Half a century later, Machine Learning has pro-
gressed from using computational power combined with human knowledge in solving problems to playing
chess without human knowledge being used, where it has produced novel strategies. Protein structures
are being solved by Machine Learning based on human-derived knowledge but without templates. There
is much promise that programs like AlphaFold based on Machine Learning will be powerful tools for
designing entirely novel protein folds and new activities. But, will they produce novel ideas on protein fold-
ing pathways and provide new insights into the principles that govern folds?
Ó 2021 Elsevier Ltd. All rights reserved.

Introduction dynamics and to aid the visualization and

Machine Learning has had a significant impact on
what I do in science and in my personal activities.
My career in research as a protein scientist began
at a most fortunate time. I was recruited in the last
year of my PhD in 1968, a key year that pops up a
few times in this article, to work as a chemist on
the mechanisms of enzymes whose structures
were being determined at the MRC of Molecular
Biology. The first three-dimensional structures of
enzymes were beginning to be solved by X-ray
protein crystallography, and the determination of
their primary structures by direct protein
sequencing was laboriously progressing. The next
decade saw the introduction of recombinant DNA
technology, DNA sequencing, gene cloning and
expression, on the one hand, and the application
of computational methods to analyse protein
classification of protein structures into families. In
a parallel universe, the science of Artificial
Intelligence (AI) and Machine Learning was also
beginning to emerge as theory and potential
applications. To set the scene in this perspective, I
will begin with the little that I know about AI and
Machine Learning and how they have impacted on
two of my pastimes, board games like chess, a
passion that I share with Demis Hassabis, a
mastermind of DeepMind, the company behind
AlphaFold, and my current addiction to bird and
nature photography.
Artificial intelligence, machine learning
Artificial intelligence is the science of studying
how to build intelligent programs and machines
that can solve problems in an imaginative manner.

0022-2836/Ó 2021 Elsevier Ltd. All rights reserved. Journal of Molecular Biology 433 (2021) 167088
A.R. Fersht
We are concerned here with Machine Learning,
which is a subfield of AI that enables machines to
learn from past data or experience without being
explicitly programmed. It can use methods from
statistics and physics to find hidden insights in
data. It involves algorithms such as neural
networks and deep learning neural networks. (A
neural network is a computing system made up of
interconnected units like neurons in the brain that
processes information by passing it among them.
Deep learning uses huge neural networks with
many layers of processing units.) Machine
Learning is concerned mainly about accuracy and
patterns, and automates analytical model building.
Application to photography and board
games
Accurate autofocus is a key feature of modern
photography, especially when photographing
birds, animals and other subjects in action. When
photographing birds, animals and human faces,
having the eye in focus is usually the most
important feature. Companies like Sony and
Canon have developed AI methods for doing this.
In the past year, Canon released its first camera,
the R5, that does this remarkably well. Its
algorithms will recognise the shape of all types of
birds and animals, locate them in just a small part
of a crowded scene, home in on the head and
then the eye. It can locate and track a bird in flight
and focus unerringly on the eye at a frame rate of
20/s. Do I know how it does it? I know that it has
somehow been trained on many photos of birds
and animals, but all that concerns me is that it
works accurately and rapidly and assists me. I
could get sharp shots in the past without this aid,
but the success rate with it is far higher. The eye-
autofocus is simply a useful tool.
Chess and Go
Chess has for long been a subject of computer
science and a challenge to the practitioners of AI
but with minimal success until the first glimmers of
hope at the end of the 1960s. In 1968, David
Levy, Scottish chess champion and computer
expert, made a £500 bet with two AI pioneers that
no computer program would win a chess match
against him within 10 years. He only just won the
bet in 1978. The strength of chess playing
machines improved after the slow start and in the
mid 1990s super computers programmed on past
games played by humans and human-designed
tactics and strategy reached grandmaster
strength. In 1997, the IBM Deeper Blue defeated
one of the greatest players in the history of chess,
Garry Kasparov, 3.5–2.5 in a six-game match.
Chess engines, which are programmed with much
human experience and input, are now running on
laptops, are stronger than the top grandmasters
2
Journal of Molecular Biology 433 (2021) 167088
and are routinely used by them to analyse
positions and train. The game of Go is
computationally even more difficult than Chess
and the ability of machines to beat the best
human players was more limited until 2015.
It is perhaps no coincidence that Demis Hassabis
of DeepMind was a pre-teenage chess prodigy
before doing his degree in computer science and a
PhD in neuroscience. In 2015, AlphaGo, the
DeepMind program, beat the European Go
Champion. The program1 used deep neural net-
works, was trained by supervised learning from
human games and reinforcement learning from
games of self-play, and went on to beat the World
Champion Ke Jie. Subsequently, there was a signif-
icant breakthrough on the introduction of the pro-
gram AlphaGo Zero2 that mastered Go to an even
higher level using deep neural networks and self-
reinforcement methods without employing any prior
human knowledge: the rules of the game were set as
the parameters and the machine learned just by
playing itself and self-reinforcement. The program
was extended to master chess and shogi again just
by knowing the rules and playing itself.3 AlphaGo
Zero is easily the strongest chess playing program
by far. The program has taken a further step forward
in MuZero which works also with Atari games that
are messy and do not rely on a defined set of rules.3
So where does this leave chess and Go players?
Lee Se-dol, the only human to beat AlphaGo in a
game (due to a machine blunder), retired in
deference to the superiority of machines. But, Ke
Jie is learning from AlphaGo Zero to improve his
game. Similarly, AlphaGo Zero has brought some
new strategies into chess and is stimulating human
players who are using it to improve their play.
AlphaFold and protein folding
The Protein Folding Problem has, at least, two
parts. The first, based on the work of Christian
Anfinsen,4 is the prediction of the three-
dimensional structure of proteins from knowing only
their primary structure. The second, asked by
Levinthal in 1968: What is the pathway of protein
folding?5
Structure prediction
The first predictions of protein structure were
based on using the known, previously determined
structure of a homologous protein as a template.
For example, Keil and co-workers in 19686 mod-
elled the structure of trypsin based on the structure
of alpha-Chymotrypsin determined by Blow and co-
workers,7 a completely human-based model
building.
Fast forward 50 years of intense experimental
work and 175,000 three-dimensional structures in
the Protein Data Bank and great advances in
predicting structures fuelled by the CASP
competition, AlphaFold has exhibited the power of
A.R. Fersht
Machine Learning in recognising patterns in primary
sequences that determine three-dimensional folds
with high precision. The central component of
AlphaFold is a neural network that is trained on
the very large numbers of structures in the Protein
Data Bank to predict distributions of distances
between the Cb atoms of pairs of residues of a
protein and construct an artificial force field to
direct folding without using an individual template
but on patterns derived from many proteins.8 It
has also relied heavily on sequences databases
and multiple sequence alignments. The situation is
like with the chess programs that have much human
experience built into them and can perform better
than human beings because they use additional dif-
ferent ways of analysis and powerful computation,
or, even more crudely, like the eye-detecting autofo-
cus on my camera which is much faster and more
accurate than me. AlphaFold has not yet shown
simple rules that govern protein folding – indeed,
there may not be – or explained to me how I can
look at a protein myself and see how it would fold
up. There is even the philosophical question of
whether AlphaFold is really solving the folding prob-
lem as posed by Anfinsen: there is an alternative
view that if the method relies directly or indirectly
on the information derived from multiple sequence
alignments then it is a method of experimental
structure determination like X-ray crystallography,
NMR spectroscopy or electron microscopy, using
sequence as the experimental data. But, whatever
the philosophical arguments, AlphaFold could be
very useful technology, as for example for the
design of drugs where structural knowledge of the
target protein is often the starting point, and its
power can be harnessed by experimentalists and
theoreticians just as chess players now routinely
use the earlier generations of chess programs
based on human knowledge and machine number
crunching.
Where it goes from here will be exciting. I wrote
back in 1984 after the first protein engineering
experiments, that one of the goals was to design
novel enzymes.9 This has proved to be an immense
challenge since the interplay of structure, binding
and catalysis is so elusively exquisite and there
are very stringent and not fully understood con-
straints on enzyme-substrate and enzyme-
transition interactions and dynamics. The design
and selection of simple binding proteins, on the
other hand, is far simpler. So, can AlphaFold facili-
tate enzyme design? Will it automate drug design?
Can it design entirely novel protein folds without
input from multiple sequence alignments? And
regarding protein design, there is an additional com-
plication to predicting the structure of an existing
protein that is known to fold: a novel protein may
or may not fold as protein stability is often close to
marginal and there are kinetic barriers to successful
folding. I certainly hope they will solve these prob-
lems, and wait in keen anticipation as I am always
3
Journal of Molecular Biology 433 (2021) 167088
in awe at the skill and ingenuity of experimentalists
and theoreticians.
Folding pathways
Solving the pathway of protein folding, along with
the dynamics of protein processes, is a different
type of challenge from predicting protein structure.
A rough analogy is that structure prediction is like
equilibrium thermodynamics, which gives the
energy level of a state but no information on the
kinetics of how the state reached that energy
level. AlphaFold’s task was to predict the most
likely structures of proteins that are known to fold,
and not the kinetics and stability of folding.
The posing of the pathway problem, famously
attributed to Levinthal5,10 was, in reality, a search
for mechanisms that would speed up a process that
if unbiased and purely random would take eons.
Theoreticians have subsequently shown in general
terms and simplified simulations how the acquisition
of native contacts speeds up folding, and atomistic
simulations can mimic folding and unfolding path-
ways at high resolution. Kinetic experiments show
that many small domains fold by a nucleation-
condensation mechanism in which there is a final
or major transition state that looks like an expanded
form of the native structure with many long interac-
tions being partly formed that stabilize an extended
folding nucleus with stronger interactions being con-
solidated.11 Other small domains can form by a
more classical framework mechanism whereby pre-
formed elements of regular secondary structures
dock.12 Members of the homeodomain 3-helix bun-
dle family have a common fold, which would easily
be detected by AlphaFold. But the mechanism of
their folding slides from a framework mechanism
to nucleation-condensation with change of local sta-
bility of the secondary structure, as shown by exper-
iment and atomistic simulation.12
Atomistic simulation of the unfolding pathways of
proteins, which are the folding pathways in reverse
for simple systems, is very powerful and widely
applicable to families of proteins where methods
can be applied to detect features that direct
folding mechanisms and lead to different
sequences forming similar structures.13 Will
Machine Learning add to solving folding pathways
and dynamic processes?
Where does it leave experimentalists? Are we like
Lee Se-dol and retire to defer to superior machines
or are we going to use Machine Learning as an
invaluable tool like chess players use chess
engines? The first elucidations of three-
dimensional structures of enzymes in the late
1960s caused some classical enzymologists to flee
to work on proteins with unknown structures so as
not to compete with the new technology and its
exponents. Others saw this as the most exciting
opportunity to understand enzyme catalysis,
structure and mechanism at the atomic level and
A.R. Fersht Journal of Molecular Biology 433 (2021) 167088

grasped the new opportunities with both hands for
experiment and computation. I would hope that the
same is true for Machine Learning applied to
proteins and wish I could start my career again on
protein design with AlphaFold at my disposal.
Acknowledgments
I thank the MRC Laboratory of Molecular Biology
for funding.
Conflict of Interest Statement
The authors declare no conflicts of interest.
Received 23 April 2021;
Accepted 28 May 2021;
Available online 2 June 2021
Keywords:
protein folding;
machine learning;
chess;
Go
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