Machine Learning for Chemical Sciences

Machine Learning for Chemical Sciences
Ichigaku Takigawa
HU-SNU Joint Symposium
2018 International Workshop on 
New Frontiers in Convergence Science and Technology
Graduate School of Information Science and Technology, HU
Institute for Chemical Reaction Design and Discovery (WPI-ICRD), HU

Brief Bio: Ichigaku Takigawa
Modulatory proteolysis 
(MCP 2016)
Transcription elongation
regulation (Nat Comm 2015)
Neurodegenerative disease and
genomes (Mol Brain 2017)
Catalytic conversion of
methane (JPCC 2017)
10 years Hokkaido University
(1995-2005)
7 years at Kyoto University
(2005-2011)
7 years at Hokkaido University
(2012-2018)
PhD in Computer Science/Statistical Science
(Multivariate Analysis, Statistical Signal Processing)
• Bioinformatics Center, Institute for Chemical Research
• Graduate School of Pharmaceutical Sciences
(X-omics, Molecular Biology, Medicinal Chemistry, Biochemistry)
Research in Machine Learning & Data Mining
(ML with discrete structures, ML for sciences)

Two Approaches to Sciences
Our main interest in science: 'unknown mechanism/principle'
mechanism/principle
(unknown)
observations/data
Theory/Hypothesis-driven modeling (as in natural sciences)
explicit model observations/data
e.g. Newtonian mechanics, quantum mechanics, theory of relativity, etc.
we can run a simulation!
Data-driven modeling (as in statistics, machine learning, AI, etc)
model w/ unﬁxed observations/data
best tuned to ﬁt the given data
✓

Deduction vs Induction/Abduction
The grand aim of science is to cover the greatest number
of experimental facts by logical deduction from the
smallest number of hypotheses or axioms.
Albert Einstein
Hypothesis Experimental facts (data)
Deduction
Induction
Abduction
“Experience/Observation”
“Intuition/Serendipity”
Not logical at all
Logical
Can we somehow “rationalize” this part by using the data?

Machine Learning for Sciences
REVIEW
Inverse molecular design using
machine learning: Generative models
for matter engineering
Benjamin Sanchez-Lengeling1
and Alán Aspuru-Guzik2,3,4
*
The discovery of new materials can bring enormous societal and technological progress. In this
context, exploring completely the large space of potential materials is computationally
intractable. Here, we review methods for achieving inverse design, which aims to discover
tailored materials from the starting point of a particular desired functionality. Recent advances
from the rapidly growing field of artificial intelligence, mostly from the subfield of machine
learning, have resulted in a fertile exchange of ideas, where approaches to inverse molecular
design are being proposed and employed at a rapid pace. Among these, deep generative models
have been applied to numerous classes of materials: rational design of prospective drugs,
synthetic routes to organic compounds, and optimization of photovoltaics and redox flow
batteries, as well as a variety of other solid-state materials.
M
any of the challenges of the 21st century
(1), from personalized health care to
energy production and storage, share a
common theme: materials are part of
the solution (2). In some cases, the solu-
tions to these challenges are fundamentally
limited by the physics and chemistry of a ma-
terial, such as the relationship of a materials
bandgap to the thermodynamic limits for the
generation of solar energy (3).
Several important materials discoveries arose
by chance or through a process of trial and error.
For example, vulcanized rubber was prepared in
the 19th century from random mixtures of com-
pounds, based on the observation that heating
with additives such as sulfur improved the
rubber’s durability. At the molecular level, in-
dividual polymer chains cross-linked, forming
bridges that enhanced the macroscopic mechan-
ical properties (4). Other notable examples in
this vein include Teflon, anesthesia, Vaseline,
Perkin’s mauve, and penicillin. Furthermore,
these materials come from common chemical
compounds found in nature. Potential drugs
either were prepared by synthesis in a chem-
ical laboratory or were isolated from plants,
soil bacteria, or fungus. For example, up until
2014, 49% of small-molecule cancer drugs were
natural products or their derivatives (5).
In the future, disruptive advances in the dis-
covery of matter could instead come from unex-
plored regions of the set of all possible molecular
and solid-state compounds, known as chemical
space (6, 7). One of the largest collections of
molecules, the chemical space project (8), has
mapped 166.4 billion molecules that contain at
most 17 heavy atoms. For pharmacologically rele-
vant small molecules, the number of structures is
estimated to be on the order of 1060
(9). Adding
consideration of the hierarchy of scale from sub-
nanometer to microscopic and mesoscopic fur-
ther complicates exploration of chemical space
in its entirety (10). Therefore, any global strategy
for covering this space might seem impossible.
Simulation offers one way of probing this
space without experimentation. The physics
and chemistry of these molecules are governed
by quantum mechanics, which can be solved via
the Schrödinger equation to arrive at their ex-
act properties. In practice, approximations are
used to lower computational time at the cost of
accuracy.
Although theory enjoys enormous progress,
now routinely modeling molecules, clusters, and
perfect as well as defect-laden periodic solids, the
size of chemical space is still overwhelming, and
smart navigation is required. For this purpose,
machine learning (ML), deep learning (DL), and
artificial intelligence (AI) have a potential role
to play because their computational strategies
automatically improve through experience (11).
In the context of materials, ML techniques are
often used for property prediction, seeking to
learn a function that maps a molecular material
to the property of choice. Deep generative models
are a special class of DL methods that seek to
model the underlying probability distribution of
both structure and property and relate them in a
nonlinear way. By exploiting patterns in massive
datasets, these models can distill average and
salient features that characterize molecules (12, 13).
Inverse design is a component of a more
complex materials discovery process. The time
scale for deployment of new technologies, from
discovery in a laboratory to a commercial pro-
duct, historically, is 15 to 20 years (14). The pro-
cess (Fig. 1) conventionally involves the following
steps: (i) generate a new or improved material
concept and simulate its potential suitability; (ii)
synthesize the material; (iii) incorporate the ma-
terial into a device or system; and (iv) characterize
and measure the desired properties. This cycle
generates feedback to repeat, improve, and re-
fine future cycles of discovery. Each step can take
up to several years.
In the era of matter engineering, scientists
seek to accelerate these cycles, reducing the
FRONTIERS IN COMPUTATION
KI
onJuly26,2018http://science.sciencemag.org/Downloadedfrom
REVIEW https://doi.org/10.1038/s41586-018-0337-2
Machine learning for molecular and
materials science
Keith T. Butler1
, Daniel W. Davies2
, Hugh Cartwright3
, Olexandr Isayev4
* & Aron Walsh5,6
*
Here we summarize recent progress in machine learning for the chemical sciences. We outline machine-learning
techniques that are suitable for addressing research questions in this domain, as well as future directions for the field.
We envisage a future in which the design, synthesis, characterization and application of molecules and materials is
accelerated by artificial intelligence.
T
he Schrödinger equation provides a powerful structure–
property relationship for molecules and materials. For a given
spatial arrangement of chemical elements, the distribution of
electrons and a wide range of physical responses can be described. The
development of quantum mechanics provided a rigorous theoretical
foundationforthechemicalbond.In1929,PaulDiracfamouslyproclaimed
that the underlying physical laws for the whole of chemistry are “completely
known”1
. John Pople, realizing the importance of rapidly developing
computer technologies, created a program—Gaussian 70—that could
perform ab initio calculations: predicting the behaviour, for molecules
of modest size, purely from the fundamental laws of physics2
. In the 1960s,
the Quantum Chemistry Program Exchange brought quantum chemistry
to the masses in the form of useful practical tools3
. Suddenly, experi-
mentalists with little or no theoretical training could perform quantum
calculations too. Using modern algorithms and supercomputers,
systems containing thousands of interacting ions and electrons can now
be described using approximations to the physical laws that govern the
world on the atomic scale4–6
.
The field of computational chemistry has become increasingly pre-
dictive in the twenty-first century, with activity in applications as wide
ranging as catalyst development for greenhouse gas conversion, materials
discovery for energy harvesting and storage, and computer-assisted drug
design7
. The modern chemical-simulation toolkit allows the properties
of a compound to be anticipated (with reasonable accuracy) before it has
been made in the laboratory. High-throughput computational screening
has become routine, giving scientists the ability to calculate the properties
of thousands of compounds as part of a single study. In particular, den-
sity functional theory (DFT)8,9
, now a mature technique for calculating
the structure and behaviour of solids10
, has enabled the development of
extensive databases that cover the calculated properties of known and
hypothetical systems, including organic and inorganic crystals, single
molecules and metal alloys11–13
.
The emergence of contemporary artificial-intelligence methods has
the potential to substantially alter and enhance the role of computers in
science and engineering. The combination of big data and artificial intel-
ligence has been referred to as both the “fourth paradigm of science”14
and the “fourth industrial revolution”15
, and the number of applications
in the chemical domain is growing at an astounding rate. A subfield of
generating, testing and refining scientific models. Such techniques are
suitable for addressing complex problems that involve massive combi-
natorial spaces or nonlinear processes, which conventional procedures
either cannot solve or can tackle only at great computational cost.
As the machinery for artificial intelligence and machine learning
matures, important advances are being made not only by those in main-
stream artificial-intelligence research, but also by experts in other fields
(domain experts) who adopt these approaches for their own purposes. As
we detail in Box 1, the resources and tools that facilitate the application
of machine-learning techniques mean that the barrier to entry is lower
than ever.
In the rest of this Review, we discuss progress in the application of
machine learning to address challenges in molecular and materials
research. We review the basics of machine-learning approaches, iden-
tify areas in which existing methods have the potential to accelerate
research and consider the developments that are required to enable more
wide-ranging impacts.
Nuts and bolts of machine learning
With machine learning, given enough data and a rule-discovery algo-
rithm, a computer has the ability to determine all known physical laws
(and potentially those that are currently unknown) without human
input. In traditional computational approaches, the computer is little
more than a calculator, employing a hard-coded algorithm provided
by a human expert. By contrast, machine-learning approaches learn
the rules that underlie a dataset by assessing a portion of that data
and building a model to make predictions. We consider the basic steps
involved in the construction of a model, as illustrated in Fig. 1; this
constitutes a blueprint of the generic workflow that is required for the
successful application of machine learning in a materials-discovery
process.
Data collection
Machine learning comprises models that learn from existing (train-
ing) data. Data may require initial preprocessing, during which miss-
ing or spurious elements are identified and handled. For example, the
Inorganic Crystal Structure Database (ICSD) currently contains more
than 190,000 entries, which have been checked for technical mistakes
DNA to be sequences into distinct pieces,
parcel out the detailed work of sequencing,
and then reassemble these independent ef-
forts at the end. It is not quite so simple in the
world of genome semantics.
Despite the differences between genome se-
quencing and genetic network discovery, there
are clear parallels that are illustrated in Table 1.
In genome sequencing, a physical map is useful
to provide scaffolding for assembling the fin-
ished sequence. In the case of a genetic regula-
tory network, a graphical model can play the
same role. A graphical model can represent a
high-level view of interconnectivity and help
isolate modules that can be studied indepen-
dently. Like contigs in a genomic sequencing
project, low-level functional models can ex-
plore the detailed behavior of a module of genes
in a manner that is consistent with the higher
level graphical model of the system. With stan-
dardized nomenclature and compatible model-
ing techniques, independent functional models
can be assembled into a complete model of the
cell under study.
To enable this process, there will need to
be standardized forms for model representa-
tion. At present, there are many different
modeling technologies in use, and although
models can be easily placed into a database,
they are not useful out of the context of their
specific modeling package. The need for a
standardized way of communicating compu-
tational descriptions of biological systems ex-
tends to the literature. Entire conferences
have been established to explore ways of
mining the biology literature to extract se-
mantic information in computational form.
Going forward, as a community we need
to come to consensus on how to represent
what we know about biology in computa-
tional form as well as in words. The key to
postgenomic biology will be the computa-
tional assembly of our collective knowl-
edge into a cohesive picture of cellular and
organism function. With such a comprehen-
sive model, we will be able to explore new
types of conservation between organisms
and make great strides toward new thera-
peutics that function on well-characterized
pathways.
References
1. S. K. Kim et al., Science 293 , 2087 (2001).
2. A. Hartemink et al., paper presented at the Pacific
Symposium on Biocomputing 2000, Oahu, Hawaii, 4
to 9 January 2000.
3. D. Pe’er et al., paper presented at the 9th Conference
on Intelligent Systems in Molecular Biology (ISMB),
Copenhagen, Denmark, 21 to 25 July 2001.
4. H. McAdams, A. Arkin, Proc. Natl. Acad. Sci. U.S.A.
94 , 814 ( 1997 ).
5. A. J. Hartemink, thesis, Massachusetts Institute of
Technology, Cambridge (2001).
V I E W P O I N T
Machine Learning for Science: State of the
Art and Future Prospects
Eric Mjolsness* and Dennis DeCoste
Recent advances in machine learning methods, along with successful
applications across a wide variety of fields such as planetary science and
bioinformatics, promise powerful new tools for practicing scientists. This
viewpoint highlights some useful characteristics of modern machine learn-
ing methods and their relevance to scientific applications. We conclude
with some speculations on near-term progress and promising directions.
Machine learning (ML) (1) is the study of
computer algorithms capable of learning to im-
prove their performance of a task on the basis of
their own previous experience. The field is
closely related to pattern recognition and statis-
tical inference. As an engineering field, ML has
become steadily more mathematical and more
successful in applications over the past 20
years. Learning approaches such as data clus-
tering, neural network classifiers, and nonlinear
regression have found surprisingly wide appli-
cation in the practice of engineering, business,
and science. A generalized version of the stan-
dard Hidden Markov Models of ML practice
have been used for ab initio prediction of gene
structures in genomic DNA (2). The predictions
correlate surprisingly well with subsequent
gene expression analysis (3). Postgenomic bi-
ology prominently features large-scale gene ex-
pression data analyzed by clustering methods
(4), a standard topic in unsupervised learning.
Many other examples can be given of learning
and pattern recognition applications in science.
Where will this trend lead? We believe it will
lead to appropriate, partial automation of every
element of scientific method, from hypothesis
generation to model construction to decisive
experimentation. Thus, ML has the potential to
amplify every aspect of a working scientist’s
progress to understanding. It will also, for better
or worse, endow intelligent computer systems
with some of the general analytic power of
creating hypotheses, testing by decisive exper-
iment or observation, and iteratively building
up comprehensive testable models or theories is
shared across disciplines. For each stage of this
abstracted scientific process, there are relevant
developments in ML, statistical inference, and
pattern recognition that will lead to semiauto-
matic support tools of unknown but potentially
broad applicability.
Increasingly, the early elements of scientific
method—observation and hypothesis genera-
tion—face high data volumes, high data acqui-
sition rates, or requirements for objective anal-
ysis that cannot be handled by human percep-
tion alone. This has been the situation in exper-
imental particle physics for decades. There
automatic pattern recognition for significant
events is well developed, including Hough
transforms, which are foundational in pattern
recognition. A recent example is event analysis
for Cherenkov detectors (8) used in neutrino
oscillation experiments. Microscope imagery in
cell biology, pathology, petrology, and other
Table 1. Parallels between genome sequencing
and genetic network discovery.
Genome
sequencing
Genome semantics
Physical maps Graphical model
Contigs Low-level functional
models
Contig
reassembly
Module assembly
Finished genome
sequence
Comprehensive model
C O M P U T E R S A N D S C I E N C E
onAugust29,2018http://science.sciencemag.org/Downloadedfrom
Nature, 559 
pp. 547–555 (2018)
Science, 293
pp. 2051-2055 (2001)
Science, 361
pp. 360-365 (2018)
Science is changing, the tools of science are changing. And that
requires different approaches. Erich Bloch, 1925-2016

Machine Learning
Machine learning is a way to construct a computer program
directly by a given (large) collection of input-output examples
without being explicitly programmed.
Generic Object Recognition
Speech Recognition
Machine Translation
Super-Resolution Imaging
AI Game Players
“감사”
J’aime la
musique I love music

My Research Interest: ML with Discrete Structures
Tree/DAG Ensemble Neural Nets/Deep Learning Probabilistic Programming
• Target data themselves have discrete structures
• ML models have discrete structures or constraints
• Variables have structural dependencies or constraints
H
H
H
H
H
H
H
H
O
N
O
O
H
H
H
O
O
H
H
N
O
O
Cl
ClCl
Sets, Sequences, Combinations, Permutations, Branching Chains (Trees), Networks (Graphs), …

Molecular Machine Learning
MoleculeNet: A Benchmark for Molecular Machine Learning 
https://arxiv.org/abs/1703.00564 
https://github.com/deepchem/deepchem (https://deepchem.io/)
CH3
N
H3C
H
NS
N
O
CH3
N
OH
x
molecule property value
ˆy
ˆy = f✓(x)
Quantitative structure–activity/property relationship (QSAR/QSPR)

Many levels of interest
• Mutagenic potency
• Carcinogenic potency
• Endocrine disruption
• Growth inhibition
• Aqueous solubility
N
NH
OO
HH
H
H H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
O
O
O
O
O
O
Cl
H
H
H
H
H
HH
H
H
H
H
H
H
H
H
H
H
Br
Br O P
O
O Br
Br
O
Br
Br
H
H
H
H
H
H
H
H
H
H
HH
H
HH
N
S
N
N
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
O
N
O
O
H
H
H
O
O
H
H
N
O
O
Cl
ClCl
H
H
H
H
H
H H
N
O
O
H
H
H
H
H
H
H H
H
N
O
O
H
H
H
H
H
H
H
N
H
N
O
O
N
O
O
H
H
H
H
H
H
H
H
N
CH3
O
O
H
N Cl
Cl
Cl
Cl
Cl
H3C
O O
O
O
O
O
H3C
CH3
CH2
O
HN
O
O
NH
CH3
HO
OH
CH3
N
O
O
CH3
N
N
H
N
H
H3C
N
H3C
H3C
NH
O
N
O
NO
CH3
O N
NH2
O
CH3
Br
CH3
N
H3C
H
NS
N
O
CH3
N
OH
CH3
CH3N
N
N
CH3H3C
H2N NH2
H
OH
O
HO
CH3
H
H
O
CH3
H
O
OH3C HH
H
O
H3C
S
CH3
O
H
H
O
CH3
CH3
OO
HO
H3CH
HO
F
H
O
H3C
NH2
O
N
HO
HO
O
H
H
O
O
OH3C
O
O
O
CH3
O
CH3
HO
CH3
H
O
O
CH3
H
H
N
H
N O
H3C
O
O
O

ML Surrogates for Quantum Chemistry
http://quantum-machine.org/datasets/
Quantum chemistry structures and properties of 134 kilo molecules, Scientiﬁc Data 1, 140022 (2014)
Dataset: structure-properties pairs in the ground state  
for all 133,885 compounds with up to 9 heavy atoms of C, O, N, or F
DFT
B3LYP/6-31G(2df,p)
Structure in
the ground state
15 properties in
the ground state
http://www.nature.com/articles/sdata201422

Inverse Design (Machine Teaching)
“machine teaching”
“machine learning”
Bayesian optimization / Black-box optimization / Sequential
design of experiments / Surrogate-based optimization
“television”
Beware: Inverse is not unique??
CH3
N
H3C
H
NS
N
O
CH3
N
OH
x
molecule property value
ˆy
ˆy = f✓(x)

A lot of technical challenges, pitfalls, and potentials

Towards (Semi-)Automated Sciences?

✗
ML for Heterogeneous Catalysis
Chemical Reaction
Catalysts
Heterogeneous catalysts / Surface reactions
Haber–Bosch Process
Ferrous metal Catalysis Noble Metal Catalysis (Pt, Pd, Rh…) Various Metallic Catalysts 
(Li, rare earthes, alkaline earths)
(industrial synthesis of ammonia)
Exhaust Gas Purification Conversion of Methane
“Fertilizer from Air”
artificial nitrogen fixation

ML for Heterogeneous Catalysis
Catalyst Informatics
Large Literature Data
(in prep)
Quantum Calculated Data
(RCS Adv 2016; JPCC 2018)
Data from Controlled
Experiments (plan)
ACS 2018 [CATL]  
Machine Learning for Catalysis Research

ML for Chemical Reaction Design & Discovery
Institute for Chemical Reaction Design and Discovery (WPI-ICReDD), HU
We’ll start international hiring!!
Computational Science
Explores Quantum Chemically
Possible Reaction Paths
Information Science
Uses Various Data and Known
Information to Prioritize Paths
Experimental Science
Realizes & Validates Reactions in
Various Application Domains
The AFIR
method
2018 Oct 23-
HU 10 year project got funded

Machine Learning for Chemical Sciences
• Some words by David Hand at KDD2018@London:
• Theory-driven models can be wrong
• But data-driven models cannot be wrong or even right. 😩
• Data-driven are not trying to describe an underlying reality.
• But are merely intended to be useful. 😆
• So they could be poor or useless, but not wrong
• We need to understand the data, the models, the algorithms.
• We need to collaborate with domain experts because many
different conclusions are always possible from ﬁnite data.

Thanks for many nice people around me

Machine Learning for Chemical Sciences

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