The Development and Use of the Next-Generation Supercomputer Project of the Ministryof Education, Culture, Sports, Science and Technology (MEXT).

Next-Generation Integrated Simulation of Living Matter

BioSupercomputing
Newsletter 4
Vol.

2011.2

Participants in the winter school 2011 forthe Integrated Simulation of Living Matter(See pages 10 and 11 of the text)

CONTENTS●SPECIAL INTERVIEW ◦In order to change from observation-type medical practice focusing on experience toprediction-type medical practice to construct the base of theoretical medicine

Professor, Department of Internal Medicine (Cardiovascular Medicine), Director of the Metabolic Disease Research Center, 2-3
Bio-Research Medical Center, Tokai University Graduate School of Medicine, and Director, Department of Metabolic System
Medicine, Tokai University General Medical Laboratory Shinya Goto

◦It is expected that new possibilities in nutrition science and health control will be opened upby simulation science
EXECUTIVE PROFESSIONAL Health infomatics DEPT., Ajinomoto Co., Inc. Toshihiko Ando
●Report on Research ◦The functions of a multidrug discharging transporter were verified
by coarse graining molecular simulation (Molecular Scale WG)
Graduate School of Science, Kyoto University Shoji Takada ／ Xin-Qiu Yao ／ Hiroo Kenzaki◦Cell simulation considering time-space (Cell Scale WG)
Computational Science Research Program, RIKEN Yasuhiro Sunaga◦Development of HIFU simulator for non-invasive treatment with high-intensity focused ultrasound(Organ and Body Scale WG)
VCAD System Research Program, RIKEN Kohei Okita

4-5
6
7
8

◦PLATO: Platform for a collaborative brain system modeling toward development of large scale mathematical model.
(Brain and Neural WG)①Computational Science Research Program, RIKEN●Report②Brain Science Institute, RIKEN

Keiichiro Inagaki①／ Takayuki Kannon②／ Nilton L. Kamiji②／ Koji Makimura②／ Shiro Usui ①②◦Report on the workshop in BMB2011 (Joint Meeting of the 33rd Congress of the Molecular Biology Society ofJapan and the 83th Congress of the Japanese Biochemical Society)◦Winter School 2011 for the Integrated Simulation of Living Matter
Computational Science Research Program, RIKEN Yasuhiro Ishimine (Organ and Body Scale WG)
The Institute of Medical Science, The University of Tokyo Hidetoshi Urakubo (Brain and Neural WG)
Computational Science Research Program, RIKEN Yasuhiro Sunaga (Cell Scale WG)
Computational Science Research Program, RIKEN Gen Masumoto (High-Performance Computing Team)
Computational Science Research Program, RIKEN Keiji Misawa (Data Analysis Fusion WG)
Computational Science Research Program, RIKEN Hisayuki Miyashita (Molecular Scale WG)●ISLiM Participating Institutions / Event information / Event report

9
10

11

12

S

PECIAL INTERVIEW

Future of Life Science Pioneered by Biosupercomputing

In order to change from observation-type medical
practice focusing on experience to predictiontype medical practice to construct
the base of theoretical medicine

Professor, Department of Internal Medicine (Cardiovascular Medicine), Director of the Metabolic
Disease Research Center, Bio-Research Medical Center, Tokai University Graduate School of
Medicine, and Director, Department of Metabolic System Medicine, Tokai University General
Medical Laboratory

Shinya Goto
■ For predictive, individual and“prospective”
medical practice━ You often say that the present medical practice is empirical,
and lacks logic and predictability.
●Goto（dispensed with the Mr. and Mrs） If I, as a clinician engaged in thetreatment of a large number of cardiovascular diseases, say this, patients
may be shocked, but it is the present state of affairs that when doctors
provide medical care, they do not fully appraise the system of the humanbody and disease scientifically, and do not provide medical care based on
definite prediction like controlling an atomic power plant based on physicalunderstanding, for example. Medical intervention based on an essential
and sophisticated understanding of life phenomena is presently impossible.
It is obvious considering the history of medical progress. Doctors know
empirically what will happen if they do nothing for diseased people. Bymaking a certain intervention considered to be effective without leaving
patients as they are and observing whether the prognosis (catamnesis) isgood or bad, we are repeatedly evaluating the propriety of intervention.
Medical care has progressed by repeatedly comparing what result will beobtained if some other intervention is made. Evaluation of experience may
be performed based on the doctor’s own common sense, or based on anumerical database obtained by summarizing a large number of cases. The
latter method for evaluation of a numerical database based on a certain
standard is also called "Evidence-Based Medicine". However, even EvidenceBased Medicine which has incorporated scientific methodology is only amethodology in which cumulative past experience is quantified. Even if
the experience is converted to a numerical database, there is no essential
difference in that past medical practice still decides future directionality
based on “retrospective” experience.
Comparing this to the history of the development of physics, it can besaid that present medical science is still in the age of Galileo. By droppinga heavy ball and a light ball from a high place at the same time, Galileo
revealed that the time taken for falling is not related to the weight ofobject. He revealed the basics of dynamics by an experiment, but he could
not arrive at a future unified principle, that is, the gravity of the earth andthe law of gravitation even control celestial motion. Before long, Newton
extended the law of gravitation by mathematically discussing the motionof objects discovered by Galileo et al., and constructed the basis of modern
physics. Current medical practice is conducted under circumstances where
the universal life phenomena controlling the human body are not yet
understood. Doctors only describe the patients’ symptoms appearing asa change in life phenomena and their change according to the presenceor absence of therapeutic intervention, and accumulate experience. Since
we can understand only the “result with or without medical intervention,”
we only evaluate the patient population to determine the propriety of
medical intervention. In order to introduce modern physics and science
like chemistry into the world of medical care, it is necessary to understandthe nature of life phenomena, to clarify the factors defining individual
differences, and then to construct learning like architectural and prospective“theoretical medicine.” Hence, it is necessary to resolve life phenomena
into factors, and to understand them by fine mathematical expression of
the causal relationship among factors. In the world of medical practice,a learning system is required which makes “theoretical prediction” and“individualization” possible. If we cannot have such a system, we will not
be able to take even one step beyond the medical practice evaluated by

2 BioSupercomputing Newsletter Vol.4

accumulation of past experience.

━ Why can we give only empirical medical care?
● Goto In a word, the nature of the problem is that, since the life
phenomena constituting the human body are too complex and there
are too many factors involved in the onset and progress of disease, wecannot precisely understand the causal relationship among these factors.
In order to give the optimum treatment for individual patients, we have tounderstand the nature of life phenomena, the factors defining individual
differences, and the sophisticated causal relationships among them. Genes,a design blueprint of an individual, are different individually, and exposure
to environment and life style are different individually. Unless the system,from molecules through cells to the human body, that is, what disease islikely to occur in the human body when a person with a certain gene lives
under a certain condition, can be understood architecturally, it is impossible
to conduct medical practice and individual medical care with which the
future can be predicted scientifically. In order to understand a system where
the combination of slight positional differences in an enormous number ofgenes individually defines optimized therapeutic methods, moreover, it isnecessary to handle an enormous amount of integrated time-dependent
information such as information about genes, exposure to environment, life
style and disease, at the same time. In order to reconstitute clinical medicine
as information science, that is, the basis of a precise future-type medical
practice in the 21st century, a high-speed supercomputer is absolutely
required. We already know information about the design blueprint of thehuman body defining individual differences called the personal genome.
We understand the system in which the design blueprint produces proteins.
However, we have not understood the system in which those proteins
constitute cells. It is the current state of affairs that although we canunderstand how the functions of biological molecules will change when adrug consisting of molecules is administered, we cannot understand how
the change is constituted in cell response and biological response on thescale of the human body. If we understand the system in which cells andthe human body are constituted by physical and chemical interactions of ahuge number of molecules, we may be able to understand life phenomena
exactly. By so doing, it may be possible to provide scientific treatment in thetrue sense for the first time.

━ What is the most promising point of the ten quadrillion
speed computer “Kei”?
● Goto In order that we can understand life phenomena, I thinkthat reproduction of life phenomena is important. If all the substances
constituting one cell were arranged positioned spatially, it might be possible,
in principle, to reconstitute the cell. At the present time, there are too many
substances that make up cells, and we have no fundamental technique thatcan reconstitute the information. If we establish a technique to measure
information about the arrangement of substances in cells precisely andenter the information virtually on a high-speed supercomputer, it should bepossible to reproduce virtual cells. We can observe the aspect whereby cells
gather together to constitute tissues and organs at the microscopic level.
Such an approach is the basis of simulation biology, and the ten quadrillion
speed computer is an important tool to realize it.
Another thing that we hope to do is to make a lot of doctors and healthprofessionals understand that past medical practice and medical science
are only an accumulation of experience, and do not offer any understandingSPECIAL INTERVIEW
of nature at all. We can do this by showing examples of thepossibility of predictable medical practice and individual medicalcare using a ten quadrillion speed computer. Moreover, they may
be able to understand that “future life science, medical practiceand medical science will proceed in such a direction.” Even if I say
that “the present time is at the stage of Galileo,” the people inclinical practice cannot understand this. If we can show concrete
examples, however, I believe that our message, “we have to change
our thinking in the future”, can be delivered.

■ Research and development of platelet
cell simulator

Platelet cell

(2 to 5µm in diameter)

Intracellular
metabolism, signal(nanometer scale)①Adhesion of GP1bα②Calculation of the rangeof activation of GP IIb/IIIa③Adhesion to the damaged site

④The range of activationof GP IIb/IIIa enlarged⑤Platelet aggregation⑥Activation of GP IIb/IIIa

Impact ofblood streamor blood cell

━ What is the platelet cell simulator that you are
addressing now?
● Goto Platelet cells are divided by voxels, and the properties
of subcellular organelle and membrane protein are included ineach voxel to reconstitute platelet cells. If the number of divisions
is increased, it can be expected that it can be reduced to a single
cell. As concerns the adhesive protein of a cell membrane, at thepresent time, we are aiming at coupling with information aboutadhesiveness obtained in a molecular scale structural analysis. Since
treatment with antiplatelet drugs for prevention of recurrence of myocardial
infarction that we provide as clinicians is intervention to molecules suchas cyclo-oxygenase in platelets, platelet membrane protein and receptor
protein, we are aiming at a simulation of how molecular scale intervention
with a drug may change the behavior of platelet cells. Finally, I want tosimulate whether or not organ-perfusing arteries which perfuse importantorgans such as the heart and brain may be thrombotically occluded byaggregation of a large number of platelet cells, and whether or not theocclusion can be inhibited by intervention with a drug of molecular scale.
As for the molecules constituting platelet cells, moreover, there aremolecules with obvious biological characteristics such as adhesive proteins
having special adhesion modes. I therefore think that the platelet cell
simulator will be useful for combination of the molecular scale with the cell
scale. Since it is known that aggregation of a large number of platelet cells
may cause myocardial infarction, moreover, the simulator will promote a
combination of the cell scale with the organ and body scale. Moreover, thisis a system to prepare the basis of a 2-step coupling of the molecular scalewith the cell scale, and the cell scale with the organ and body scale, mainlywith platelet cells, by coupling the associations between molecules andplatelet cells theoretically by simulation, and by quantitatively simulating
the process in which platelet cells of micrometer scale lead to occlusion ofblood vessels of millimeter scale, that is, the impact of cells on the organs
and body.
A platelet cell has no nucleus and is not divided. Moreover, there is lessproduction of new substances. Its function is specialized in hemostasis
and thrombus formation. Since platelet cells have a simple structure andfunction, it is suitable for reproduction by simulation. I will show an actual
example using platelet cells. Moreover, it is clear from clinical studies thatplatelet cells are importantly involved in the onset of myocardial infarction
and cerebral infarction and that, if the function of platelet cells is reduced,
the onset of myocardial infarction and cerebral infarction is inhibited. Fromthe viewpoint of clinical medicine, the association of the intervention witha drug on the molecular scale and the outcome of the organ and body scale
are obvious. Finally, whether or not a correct simulation can be performed
from the viewpoint of physics and technology is important. However,biological cells are very complex, and it is very difficult to perform a precise
simulation. Collection of actual information in the body and modeling it
on a computer should progress like two wheels of a cart. It cannot be said
that the information to be entered into the computer is sufficient, and its
quantitative capability is also low. Platelet cells are relatively easily handled,
but this is a very difficult challenge as a project.

━ What is the most difficult thing in developing a simulator?
● Goto I recognize that the biggest problem is that we have notunderstood the whole picture. Even if Kei becomes available, it is still
impossible to reproduce the complex biological body. A certain simplification⑦Desorption when the adhesive poweris weaker than the power induced byblood stream

From platelet aggregation topathological symptomatic thrombotic
disease (millimeter scale)is essential. Simplification by us who have not understood the whole picture
may be beyond the mark. Since calculation resources are limited, we are
selecting the information to be omitted in our brain. You might thinkthat the computer is fully automatic, but it is the human brain that enters
important information to make a model. Our worst problem is that we do
not know whether or not modeling can be done by selection of appropriate
information. Comparing the secret of the human body pursued in medical
science to the secret of the universe, I do not know whether, in the vast
universe, our current anxiety is because we only know the circumference ofthe earth, we only know the solar system, we only know up to the galaxy,or we actually know a considerable amount. Even if we only knew up to thesolar system, it might still be possible to clarify the basic principle controllingthe universe. At the present time, we have to try to predict the phenomenaof the human body and the outcome of disease using a principle which
we definitely understand. By substantiating the validity of the predicted
result, the validity of the prediction will be confirmed. In simulation scienceon a subject that has not revealed its true aspect, it is essential to repeat
prediction and substantiation. It is a challenging academic field from theviewpoint that the validity of modeling is repeatedly being confirmed,
while the truth has not yet been observed. I am a clinician and actuallyprovide medical care. I actually feel that much of clinical practice depends
on my experience and feeling. Although we cannot find a scientificrationale, moreover, we are practicing individualized medical care basedon my experience and feeling. I am always puzzling over how to select thedirection in which we should go for logical performance and digitization ofindividualized medical science, not based on science conducted empiricallyby a lot of doctors.

━ How about the reaction of medical practice to yourapproach?
● Goto I think that the meaning of what I want to show can beunderstood by everybody. Particularly, the leaders in academic societies
say, “certainly, we have to go in such the direction.” The leaders in global
academic societies commonly recognize that the method called EvidenceBased Medicine, that is, a scientific approach to medical practice by building
a numerical database by accumulating present experience, has got stuck.
Medical practice and medical education are suffering from a flood of
information to the numerical database of experience. It is difficult to gethealthcare professionals to change their mind and realize that predictive andindividual medical care is required. In order that the validity of our approachis understood by healthcare professionals, moreover, it is important to show
an actual example of antiplatelet treatment using a platelet cell simulator as
an example. I want a lot of people to understand that even life phenomena
are ultimately an accumulation of physical and chemical phenomena, andits descriptive term is mathematics. Moreover, I expect that young doctors,
researchers and students will participate in the field of simulation medicine.
I think that the quadrillion speed computer is the gateway to it.

BioSupercomputing Newsletter Vol.4 3

S

PECIAL INTERVIEW

Future of Life Science Pioneered by Biosupercomputing

It is expected that new
possibilities in nutrition scienceand health control will be opened
up by simulation science
EXECUTIVE PROFESSIONAL
Health infomatics DEPT., Ajinomoto Co., Inc.

Toshihiko Ando
■A new viewpoint born from simulation━ You have played a central role in the Life Sciences
A p p l i c at i o n Su b co m m i t te e M e e t i n g o f t h e I n d u s t r i a l
Committee for Supercomputing Promotion. Have you always
been interested in simulation?
● Ando（dispensed with the Mr. and Mrs） Describing the present stateof affairs, it can be said that there are very few cases using simulation in
the food industry. For example, in heating frozen food, simulation has
been performed to develop the form of tray with the best heat efficiency,
and simulation has been used to design the manufacturing processes forfoods. However, the Research and Development Division of this company
is addressing research and development on an “Amino index” useful for
health control by measuring the concentrations of amino acids in the blood.
This aims at development of new products using amino acids and at newcommercial prospects such as providing information useful for healthchecks and diagnosis of disease, and prediction of drug efficacy and adverse
reactions, based on an idea that health conditions can be analyzed using
the pattern in the concentration of amino acids, the center of the metabolite
network (aminogram), as an index. I am also engaged in this research anddevelopment, in which I thought that I can make good use of simulation.
For example, the pattern of amino acids in the body changes when weare getting sick. The reason for this change has not been clarified, but theamino acid balance changes because a certain amino acid increased oranother amino acid decreases. It is very difficult to understand the change inbalance and its mechanism, but it may go smoothly by using simulation. So,
I am looking forward to doing research and development on a metabolism
simulator at the cellular level, which has been progressing in the field of
biosupercomputing.

━ It’s certainly different from medical science, but it may
be possible to utilize simulation for nutrition science anddevelopment of health foods.
●Ando I may get scorched by the doctors of nutrition science, but I thinkthat the teaching in nutritional science has not changed much from thepast. I think that it is very important that a new viewpoint using simulation iscreated in the field of nutrition science.
As written in the book by Mr. Shinichi Fukuoka, “Dynamic Equilibrium,” thehuman body is totally replaced in 3 or 4 months. As concerns amino acids,
firstly, we take protein from foods in an amount of about 70 g per day. It isdigested, decomposed and absorbed into the blood, and by this, about 180
g is synthesized into proteins such as for muscle tissue. On the other hand,about 180 g is decomposed to amino acids, and about 50 g is pooled as
free amino acids in the body, 45 g of which exists in cells, about 5 g of which
exists in the intercellular space and about 1 g of which exists in the blood.
They are in this kind of balance. In this cycle, moreover, 70 g is discharged
together with feces and urine through the blood (see Figure). Moreover,this cycle is totally renewed in 3 or 4 months. Amino acids which we ate
are not used as amino acids as they are, but metabolized in various ways to
become organic acids or amines and taken into the body. There is such afast metabolic turnover, but the form of the human body does not change.
The same form can be maintained, that is, equilibrium is maintained. It is

4 BioSupercomputing Newsletter Vol.4

a dynamic equilibrium. I myself think that amino acids are present at thecenter of this dynamic equilibrium, and in any case, the protein turnoveris very important. It can be said that it supports the equilibrium of body.
The turnover is very fast, but there is only 1 g of amino acids in the blood.
A person weighing 50 kg has about 10 kg of muscles but has only 1 g in the
blood. One part per 10 thousand. Even so, a constant level is maintained,
and amino acids are maintained in equilibrium. It may be good if nutrition
science were not limited to calories by a thorough understanding ofsomething like this.
My other interest is chrononutrition. In a simple term, nutrients aredifferent according to the time of intake, and the timing is important. For
drugs, there are some doctors studying when a drug shows least adverse
reactions and highest efficacy, before sleeping at night or at waking up in
the morning, considering the pattern of drug metabolism. Similarly, there
are some doctors of nutrition science studying when and how to take foods
effectively to maintain health in balance. I feel that simulation may be usefulin the field of new nutrition science to which the concept of time is added.
If we can simulate the change in the metabolism of the human body withtime when a perturbation like eating some food occurs, we may be able toprovide information concerning the nutritional management suitable for a
person, such as what nutrients are the most efficient and good for the bodyand when they should be taken. Moreover, nutrition and metabolism arevery complex, and there are many molecules involved, so it is very difficult
to control them. Their balance may be changed by something, but it isimportant to maintain it. If such a thing were clarified by simulation, I thinkthat it would be very useful for many reasons.

■Health simulator can also be realized━ The use of simulation in nutritional management is also a
new viewpoint.
● Ando Mainly in Europe, nutritional societies around the world are
addressing a campaign called “Fight against all malnutrition”. Malnutrition isconsidered to be a problem of developing countries. Apparently there are amany cases leading to malnutrition because of poverty and food shortage,
but in countries like Japan, there may still be some malnutrition. There are amany elderly people with malnutrition. For example, there are many people
who cannot eat because of decreased digestive function and loss of desire
to eat. Moreover, there are some people who come to suffer malnutrition
due to dietary limitation for lifestyle-related diseases. Simulation may be
used for research concerning what parameters we should control to prevent
malnutrition.
It is of course important to cure illness, but I think it is very important tomaintain the body in health as long as possible. In this respect, I think thatsimulation can help. For example, health care to identify some parametersuch as a health barometer and to provide a method to maintain individual
health may be acceptable. It is like a dream, but I hope for a system inwhich, if my parameter data is determined every 3 months or 6 months andanalyzed, various prescriptions to maintain my health would be identified.
If this were made visible, it might be more interesting. How about such ahealth simulator? If several tens of millions of people could register to collectSPECIAL INTERVIEW

data, a health trend might emerge, and we might be able to issue a “healthforecast” that it is necessary to prepare for some disease in the future. It
may be interesting if the whole world of industry were to address such an
attempt.

■ The world of industry may move if we canshow evidence of success.
━ Do you feel that the reaction of the world of industry tosimulation is still weak?
● Ando I think so. I think it is different depending on the field. There aremany companies working hard in the field of making things. Generally
speaking, however, in order that simulation is utilized in the world ofindustry, I think it is very important to achieve not only academic results
but also economic effects. Unless everybody understands that major
successes will be obtained by using simulation, they may think that “it may

be difficult to use it.” I think it is necessary to show some example of a major
economic success. Every category has a rule for success. Unless we can show
a paradigm of success cases using supercomputers to become winners, I feelthat the number of people who use supercomputers will not much increase.
A lot of success cases are not required. However, it might be OK if there were
only one case of major success. I hope that the present field of life sciences
will reveal such a case. If we focus on possible cases for promotion instead ofwide and shallow promotion and achieve results which might turn out to bea breakthrough, the awareness of the world of industry may change.

Moreover, it may be difficult to use supercomputers abruptly. I think that thehurdle is too high. We need a certain mechanism like a “trial system.” In sucha context, it is necessary to design a way of collaboration between industry
and the academic world. It may be necessary to examine how each area ofspecialty is used amongst ourselves, such that simulation is entrusted to theacademic world.

Dynamic equilibrium of amino acid metabolism: Proteins in the bodyare replaced with amino acids, etc. taken from foods in a few months.

Food

70g
/day

180g
/day
In the plasma: 1 g

Free amino acid pool
Intracellular: 45 g
Urine
Feces

70g
/day

10kg
of protein

Intercellular: 5 g
180g
/day

Body weight of 50kg

BioSupercomputing Newsletter Vol.4 5

Report on Research Molecular Scale WG

The functions of a multidrug
discharging transporter wereverified by coarse graining
molecular simulation
Graduate School of Science, Kyoto University(From the above) Shoji Takada, Xin-Qiu Yao, and Hiroo Kenzaki

Multidrug resistance where most drugs become ineffective leads to serious
social problems in nosocomial infection and cancer chemotherapy, etc.
This multidrug resistance arises due to different mechanisms. In the caseof Pseudomonas aeruginosa which was a large problem in nosocomial
infection, the main cause of multidrug resistance was that expressionof a multidrug discharging transporter of RND type in Pseudomonas
aeruginosa increases and discharges antibiotics from the bacteria. The
multidrug discharging transporter of RND type is driven by transfer of
H+ (proton) using the difference in acidity (pH) inside and outside cells,
and discharges the drug by using this ability. The atomic structure of the
Escherichia coli-derived RND type multidrug discharging transporter“AcrB” was elucidated by Mr. Satoshi Murakami (presently Professor ofTokyo Institute of Technology), et al. using X-ray crystal structural analysis
in 2002 and 2006. In the structural analysis done in 2002, it was shown that
AcrB is a trimer of 3 similar molecules, having three-fold symmetry, whilein the structural analysis in 2006, it was found that each molecule has thefunction of a membrane proton transporter and drug discharger, and thatthe trimer of AcrB has an asymmetric structure. In the first molecule of thisasymmetric AcrB trimer structure, a route considered as an entrance for the
drug facing into the cell opens (incorporation type), in the second molecule,the drug binds to the center (binding type), and in the third molecule, adrug discharge port facing outward from the cell opens (discharging type).
Murakami et al. considered that the 3 molecules of the AcrB trimer discharge
drugs by mediating these 3 functional states in turn. Since it seems that thewhole structure rotates 120 degrees by changing the respective states of the
3 molecules step by step, this mechanism of drug discharge was named a“functional rotation mechanism.” However, since the verification experimentusing this experimental system was difficult, it was impossible to verify thishypothesis.
We have independently developed a technique for coarse graining
molecular simulation of biomolecules as part of the project “Research andDevelopment of Next-Generation Living Matter Integrated Simulation
Software” of the Ministry of Education, Culture, Sports, Science andTechnology. In this research, we conducteda functional simulation attributable tofluctuation of the multidrug dischargetransporter AcrB by applying this newtechnique.
(1) Functional rotation of AcrB trimer anddrug discharge: In the asymmetric AcrB
trimer structure, when a proton binds tothe drug-bound AcrB molecule (blue on theleft side of Figure 1) from the extracellularspace, the drug is discharged outward(center of Figure 1), and subsequently, theother 2 AcrB molecules also changed theirstate, and a functional rotation occurred(right side of Figure 1). By this, it was shownthat functional rotation occurred according
to proton binding and that drug discharge
could occur.
(2) Resting state of AcrB trimer: It was
found that, if a drug is removed from theasymmetric AcrB trimer structure, thestructure having three-fold symmetr y
becomes stable. This structure is near
the structure elucidated in 2002. That is,
the structure obtained in the structural
analysis in 2006 is a snapshot of the way the
AcrB trimer discharges the drug, and the structure in 2002 is considered tocorrespond to the resting state.
Reference
Xin-Qiu Yao, Hiroo Kenzaki, Satoshi Murakami & Shoji Takada, Drug export and allostericcoupling in a multidrug transpor ter revealed by molecular simulations “Nature
Communications. 1, 117 (8 pages) (2010)

AcrB trimer
OutsideMembrane
Inside of cellProton binding to the drugbinding molecule (blue)
Proton H+

Structural change in molecule(blue) and discharge of drug
(purple) outward

Functional rotation occurs due tostructural change of the remaining 2
molecules (red and green).

Drug
Figure 1 : Drug discharge and functional rotation of AcrB due to proton binding
The AcrB trimer is of asymmetric structure. In the first molecule, the route considered as an entrance for the drug, which faces into the cell, opens (green
in the left figure: incorporation type), in the second molecule, the drug binds to the center (blue in the left figure: binding type), and in the third molecule,the drug discharge port facing outward opens (red in the left figure: discharging type). When a proton binds to the second drug-binding molecule fromthe outside of a cell (arrow of dotted line in the left figure), the drug of this molecule is discharged to the outside of the cell (figure at the center), and theother 2 molecules change their states (right figure).

6 BioSupercomputing Newsletter Vol.4

Report on Research Cell Scale WG

Cell simulation consideringtime-space

Computational Science Research Program, RIKEN

Yasuhiro Sunaga

All living things consist of units called cells. More than 10 million kindsof living things including single-cell organisms such as Escherichia
coli and multicellular organisms such as humans exist on the earth,and the functions and forms of cells are different so that they are
optimum for their living things survival. However, it is known thatliving things basic living cell functions have many things in common.
A cell has a very complicated and compact structures, and in the cell,
various biochemical reactions occurs actively for each compartment
which is known as an organelle. Due to this, molecules and reactions
are differentiated to implement various living functions efficiently.

Chemical reaction
present

Chemical
reaction absent

Chemical reaction
present

Chemical
reaction absent

So far, much cell simulation research ignoring cell structures has been
done by grinding up organs, the aggregates of cells, to understandthe biological systems of organisms and to explore methodsof treating diseases. In the cells, life is maintained by complex
phenomena such as biochemical reactions (metabolism) andsignaling. To reproduce these biochemical reactions, many simulators
Chemical reaction
Chemical reaction
ChemicalChemicalwere developed, and it became possible to replicate intracellularpresent
present
reaction absent
reaction absent
metabolism and signaling. However, these simulators calculate a
nondimensionalized field and replicate a chemical reaction uniformly
Figure 3: Time-course of Ca2+ concentrations (volume rendering)in the cell, a so-called 'closed bag'. In actual cells, biochemical
reactions differ for each organelle, and uneven reactions go on in thecell depending on the intracellular transfer of substances, inside andare an important location for biochemical reactions such as metabolism. We
outside the cell, and entry and exit of substance from and to the inside andprepared three-dimensional Volume data from microscopic images to use
outside of the cell. We, the Cell Scale Research and Development Team, havein the present calculation (Figure 2). We established 10 molecules involved
been looking at these things, and are now developing the RIKEN Integrated
in buffering reactions in the cell and 24 biochemical reactions. A channel
Cell Simulator (RICS) which aims to perfect an intracellular time-spacepassing Ca2+ only was localized in part of the cell membrane shown by ansimulation. With this system, we undertook a coupled analysis of intracellular
arrow in Figure 2, and simulated by influx of Ca2+.
biochemical reactions and substance diffusions with the equations ofreaction diffusion. This system uses the voxel analysis framework developed
The result of simulation is shown in Figure 3. When the buffering reaction
by the VACD research program of RIKEN for spatial expression, which is aof Ca2+ in the cell was set up (expressed as "reaction present"), the apparent
simulation system that can represent the special complex space structures
diffusion speed of Ca2+ in the cell was decreased as compared with the caseof the cell.
of no biochemical reaction (expressed as "reaction absent"). This suggested
that kinetics of Ca2+ close to that in actual cells can be simulated.
With this system, using the cell morphology obtained from actual
microscopic data, we simulated the transporters, reactions and diffusion ofThis RICS makes it possible to calculate the phenomena occurring in cells
calcium ion (Ca2+) in the cell. As concerns the cell morphology, we acquired
such as biochemical reactions and diffusions, considering their location. In
the cell morphology and the form of the nucleus and mitochondria withthe future, we want to model various cell functions, and to show that thea confocal laser microscope using a HepG2 cell, human liver-derived cells
model can be utilized to elucidate the cause of drug reactions and disease.
(Figure 1). The nucleus is the largest structure in the cell, and it packs DNA.
Moreover, we want to make this system a tool that can examine a mass of
Mitochondria have the function of producing energy for cellular activity, andcells that functions as a tissue.

Mitochondria Nucleus

Figure 1 : Cross section imageof a cell photographed using
a confocal laser microscope

Figure 2 : Cell morphology
reconstructed threedimensionally fromsuccessive cross section
images of cells

Cell membrane Merge

BioSupercomputing Newsletter Vol.4 7

Report on Research Organ and Body Scale WG

Development of HIFU simulator for
non-invasive treatment with highintensity focused ultrasound
VCAD System Research Program, RIKEN

Kohei Okita
physical model. For realization of a highly precise and non-invasive HIFU
An ultrasonic imaging diagnostic system with which the inside of thetreatment in the near future, we will contribute to the design and control
body can be investigated using inaudible ultrasound has been widelyof a HIFU system, and clinical studies for approval and examination of aused in clinical practice. There is a therapeutic method by which
preoperative treatment plan, etc., using the HIFU simulator.
ultrasound stronger than that used in this ultrasonic imaging diagnostic
system is focused on a target such as a tumor to necrotize tissues by
References
heating, which is referred to as HIFU (High Intensity Focused Ultrasound).
1. Okita K., Ono K., Takagi S., Matsumoto Y., “Development of High Intensity Focused UltrasoundThe main characteristic of HIFU is that treatment can be performed
Simulator for Large Scale Computing,” Int. J. Numer. Meth. Fluids, Vol. 65, pp. 43-66, 2011.
without incision, and the low impact on the body is of great advantage.
2. Okita K., Ono K., Takagi S., Matsumoto Y., “Numerical Simulation of the Tissue Ablation in HighIntensity Focused Ultrasound Therapy with Array Transducer,” Int. J. Numer. Meth. Fluids , Vol.
The treatment of uterine f ibroids and prostatic hyperplasia with
64, pp. 1395-1411, 2010.
therapeutic equipment using this HIFU has already been approved in
3. Fink M., Montaldo G., Tanter M., “Time-reversal acoustics in biomedical engineering,” Annu.
other countries, and clinical studies on the treatment of liver tumors, etc.,
Rev. Biomed. Eng ., Vol. 5, pp. 456-497, 2003.
are being conduced and awaiting application for approval, but someproblems remain. In the treatment of a deep-seated liver tumor,
for example, the ultrasound transmitted from the HIFU system runs
from the skin through organs such as fat, muscles, bones and liver
to a focal point (right side of Figure 1). At this time, the ultrasoundmay be absorbed so that it decays when it passes through variousorgans, the ultrasound may be refracted so that it bends, and partof the ultrasound may be reflected. Thus, in treating deep-seatedtumors with HIFU, the energy required to heat the target may beinsufficient due to decay of the ultrasound, the focal point may
be blurred because of reflection or refraction of the ultrasound,and the position of the focal point may deviate from the target. In
order to control the HIFU system so that the ultrasound focuses on
Figure 1 : HIFU simulation of liver tumor using a numerical human body model
the target, it is therefore necessary to know how the ultrasoundThe figure on the rights shows the distribution of tissues lying in the path of ultrasoundpasses through the body, and using the biological informationtransmission.
obtained by CT or MRI, we are trying to reproduce the behavior ofultrasound transmission in a biological body by simulation.[1]So far, the result of a simulation of HIFU treatment for a liver
tumor has been obtained as shown in Figure 1.[2] It is seen that theultrasound sent from the HIFU system is transmitted in a complex
way as shown in Figure 2, and focuses short of the target. In sucha case, the normal part is heated instead of the site of tumor to
be treated. In order to focus the ultrasound onto the target bycontrolling the ultrasound delivered by the system, a method
called the time-reversal method [3] is therefore used. The timereversal method is to emit ultrasound from a sound source placedat the target point, to receive the ultrasound with the HIFU system,and to send the received signals by reversing the time. The resultof simulation by controlling the HIFU system by this time-reversal
method is shown in Figure 3, showing that the ultrasound focuses
appropriately on the target. When ultrasound is transmitted in
a complex way in the body as in this case, it is expected that it
will be possible to treat a deep-seated tumor more precisely bycontrolling the HIFU system. Actually, since it is difficult to placea sound source at the target depth in the body, it is possible toperform highly precise HIFU treatment using the time-reversal
method by determining the controlling parameter of the HIFU
system by simulation in advance. Since a highly precise HIFU
simulation is therefore required, we will increase the precision ofa HIFU simulator by verifying the simulation result by comparison
with experiment, and by introduction of a more advanced

8 BioSupercomputing Newsletter Vol.4

Figure 2 : Condition of ultrasound transmission (left) and the position of focal point (right)
when the HIFU system is not controlled

Figure 3 : Condition of ultrasound transmission (left) and the position of focal point (right)
when the HIFU system is controlled by the time-reversal methodReport on Research Brain and Neural WG

PLATO: Platform for a collaborative
brain system modeling toward
development of large scale
Keiichiro Inagaki
mathematical model.
Takayuki Kannon①②① Computational Science Research Program, RIKEN② Brain Science Institute, RIKEN
The elucidation of information processing fulfilled by thebrain is regarded as the most difficult problem in naturalscience. In the brain, about 100 billion nerve cells form a
network consisting of about 1 trillion contacts known as
synapses. It is thought that various information obtained
from the external world, such as vision and audition, is
processed flexibly and appropriately by this network inthe brain. The function of such complicated information
processing in the brain is being revealed mainly byelectrophysiological experiments. Together with therecent dramatic progress made in computational
science, research to elucidate brain functions from theperspective of computational science has also been
conducted by structuring part of the brain in detail asa mathematical model, and carrying out simulations.
However, it is still difficult to describe the whole brain asa large-scale mathematical model for simulation.

Nilton L. Kamiji ②
Koji Makimura ②
Shiro Usui ① ②

format and Agent, it is expected that the creator of themodel can develop a mathematical model that can bindto other models without changing most of the programcodes.
For describing the information processing underlying"vision", one of the brain functions, we are constructing
a large-scale model of the whole visual system by theapproach we have described. The human visual system
consists of eyes, optic system, retina and cerebral
cortex, where information from the external world areprocessed at these multihierarchicall sites to achieve
functions such as recognition of objects and transitionof visual lines. By constructing mathematical models
for various sites in the brain, integrating them by themethod we described and doing simulations, we hope
to visualize the information processing that occurs whenhumans look at an object, for example visual illusion
such as in Figure 2. In the future, by describing all thesites in the brain involved in “vision” in collaboration
w i t h v a r i o u s r e s e a r c h e r s i nv o l v e d i n t h i s f i e l d ,integrating them by the approach that we proposed,and performing computer simulation as a large-scalemodel of "vision" using K computer, it will become
possible to elucidate the visual information processingthat occurs in the brain.

Since a vast amount of knowledge and sophisticatedtechniques are required to construct a large-scale
brain model, it is difficult for a researcher to achieve
this by working alone. Therefore, it is consideredr ath er imp or t ant to co ll e c t an d accumulate th eknowledge obtained by the collaborative work ofvarious researchers, and to integrate it as a large-scalemodel running on a computer. We are now designing amethod to integrate the knowledge and mathematicalmodels concerning various sites of the brain
obtained from conventional physiological andcomputational research as a novel approach forconstructing a large-scale brain model. In our
approach, we are constructing an integrated
development environment consisting oftools for collecting and managing the datarequired for development and simulation ofmodels registered in the database server suchas ModelDB at Yale University and various
platforms of Neuroinformatics Japan-Node,simulators, simulation ser ver, and a result
visualization tool (Figure 1). In order to facilitate
interconnection of multiple models, we are
Figure 1 : PLATO system environment
studying and developing a data format to
PLATO consists of 4 environments including a data management tool (http://
standardize the input and output of the model
concierge.sourceforge.jp/), model development environment, simulation server
and the result drawing tool.
for data exchange, and its supporting library.
The common format, for example, would
make it possible to connect mathematicalmodels produced with different programmingl a n gua g e s a n d /o r si m u l ato r s , su c h as C
language and Python. Since the model input
and output are standardized, we can modify
and update a model into a large-scale modeland install a new mathematical model in aplug-in manner. Interconnected models are
simulated in parallel by a system called Agent.
During the simulation, data communication
between models is also adjusted automaticallyby accounting the progress of each model. By
providing a unified library for such a common

Figure 2. Configuration diagram ofa large-scale visual system model
Schematic diagram of an
integrated mathematical modelof the visual system comprisingof the eye movement, the optic
system, the retina and the cortex,
and sample image of eachmodel output at simulation. The
mathematical model at each site is
described as an individual model,
and each model is connected by
the common format (Common
data format).

BioSupercomputing Newsletter Vol.4 9

ReportReport on the workshop in BMB2010 (Joint
Meeting of the 33rd Congress of the Molecular
Biology Society of Japan and the 83th
Congress of the Japanese Biochemical Society)

The Molecular Biology Society of Japan and the Japanese Biochemical
Society are both large academic societies representing biology study inJapan which have more than 10,000 members. In 2010, particularly, theannual congress of both societies was held as a joint meeting under thename BMB2010. We, the “Integrated Simulation of Living Matter” project,held a workshop at this congress to appeal for research in the biologicalfield.
This project is a challenge for various problems in life science from theviewpoint of computational science, while on the other hand, expectations
for computational science have also been increasing tremendously in thefield of biology in recent years. This workshop was a timely project fromthese two aspects.
In this program, the major point of the project and outline of the wholeproject were explained, and then multi-scale research for life phenomena
from the micro-scale to the macro-scale was introduced.
On the day of the workshop, the conference room with a capacity of morethan 100 was so crowded that some people had to stand, which suggested
the level of interest in this project in the biology field. A question-andanswer session was also held interactively, and the project members
obtained meaningful opinions from biologists.
It is considered that the computational scientific method in life science will
become increasingly important in the future. In the future, life science, andcommunication between the experimental method and the computational
scientific method will become essential. It can be said that this workshop
played a part in the creation of such bidirectional communication.

ReportWinter School 2011 for the Integrated
Simulation of Living Matter
Computational Science Research Program, RIKEN

Yasuhiro Ishimine (Organ and Body Scale WG)

The Institute of Medical Science, The University of Tokyo
On January 6 and 7, 2011, the Winter School 2011 for the Integrated
Simulation of Living Matter in the “Research and Development of the NextGeneration Integrated Simulation of Living Matter (ISLiM)” was held. ISLiM
usually consists of a Molecular Scale Team, Cell Scale Team, Organ and Body
Scale Team, Data Analysis Fusion Team, Brain and Neural Team, and HighPerformance Computing Team. ISLiM is developing a software to perform anumerical simulation related to life science in various spatiotemporal scalesof organisms and a large scale data analysis by harnessing the full range
performance of the ten quadrillion speed computer “Kei”, aimed at researchleading to drug discovery and development of therapeutic methods.
This winter school was planned and managed mainly by young researchers
participating in ISLiM projects, and there were 48 participants. In opening
the school, Koji Kaya, a program director, made an opening speech. Next,
Ryutaro Himeno, a vice program director, delivered a lecture about how tomanage the future ISLiM.
In the next session, the High-Performance Computing Team consistingof experts in high-speed computation made a speech. Mr. Keigo Nitori
related the episode when he received the Gordon Bell Award in the price/performance section of SC in 2009 with a computer consisting of a GPU
together with Mr. Hamada, Nagasaki University. Mr. Yosuke Ohno explained
the review process of the Gordon Bell Award from the experience when
he became a finalist for the Gordon Bell Award. Also, Mr. Hiroshi Koyama
in the High-Performance Computing Team spoke harshly about theimplementation of high-performance computing with “Kei.”
The next section was held by dividing participants into 4 subcommittees. In
each subcommittee, recent research articles were selected from the 4 fields
of molecular dynamics, blood flow, brain and genome, and brainstorming
was done based on the articles. In order to climb over a fence among
teams that usually cannot meet together, members were allocated toeach subcommittee so as to crossover from their usual teams. An active
discussion was held from the viewpoint of high-performance computing.
Thereafter, a convivial party was held, a poster presentation was made, andwe had the opportunity to hear a presentation of the research carried out
by all members. The discussion continued hotly until the time for the room
expired at midnight.

10 BioSupercomputing Newsletter Vol.4

Hidetoshi Urakubo (Brain and Neural WG)

Computational Science Research Program, RIKEN

Yasuhiro Sunaga (Cell Scale WG)

Computational Science Research Program, RIKENGen Masumoto (High-Performance Computing Team)
Computational Science Research Program, RIKEN

Keiji Misawa (Data Analysis Fusion WG)

Computational Science Research Program, RIKEN

Hisayuki Miyashita (Molecular Scale WG)

First thing in the morning on the nex t day, the discussions of thesubcommittees were summarized and presented in about 15 minutes. In
the subcommittee on molecular dynamics, advances in protein research
considering the cellular environment were discussed by taking virus capsid
protein as an example. In the subcommittee on blood flow, thrombus
formation was considered as a main theme of simulation by including
platelets in simulation, aiming at infarction utilizing thrombus formation.
In the subcommittee on the brain, the real-time behavior of animals in thecat family, for example the lion, was considered, and real-time processingof multi-channel data about brain activity, and construction and its realtime processing in an internal model including a neural network, werediscussed. Moreover, there was a joke that they should search for a place
to keep lions on the site of “Kei.” In the subcommittee on the genome, analgorithm to search for a place where only incorrect consistency among
genome sequences can be obtained due to mutation was discussed. All thesubcommittees aimed at close collaboration with the High-Performance
Computing Team as to the method of computation.
In the last section, Mr. Hiroo Kenzaki, Kyoto University, talked about the“coarse-grained biomolecular modeling and simulation program CafeMol”
disclosed as one of the first runner softwares of ISLiM at the end of lastyear (http://www.cafemol.org/). Moreover, Mr. Akihiro Fujimoto, Center for
Genomic Medicine, delivered a lecture with the title “Determination andcomprehensive analysis of genome sequences in Japanese subjects using
a super parallel sequencer” published in the journal, NatureGenetics. ThisBMB2010 Workshop“Integrated Simulation of Living Matterof the Next-Generation”
14 : 30 -16 : 30, December 9 (Thursday)
at 2B Conference room of Kobe International Exhibition Hall
Organizer: Atsushi Mochizuki (Advanced Science Institute, RIKEN)
Hideo Yokota (Computational Science Research Program, RIKEN)

Ryutaro Himeno (Computational Grand challenge in next-generation supercomputers and life science
Science Research Program, RIKEN)

Yuji Sugita (Advanced Science
Institute, RIKEN)

Shoji Takada (Kyoto University

School of Science)

Makoto Suematsu (Keio
University School of Medicine)

Koichi Takahashi (Advanced

Science Institute, RIKEN)

Analysis of structural change in a membrane transport system Sec Translocon by dynamic calculationof all atoms and molecules
Research on the operative mechanism of a multidrug resistance transporter by molecular simulation
Development and application of a hepatocellular metabolic simulation considering intracellularcompartments enhanced by mass spectrometric techniques
Advanced cell simulation – Where can we go with Kei?

Shu Takagi (Computational Science
For construction of a circulatory multi-scale simulator
Research Program; The University ofTokyo, Faculty of Engineering)

research was taken up in several newspapers.
We ardently hope that the communication in this winter school will bringout the performance of “Kei”, and lead to drug discovery and developmentof therapeutic methods. At the end of the winter school, we visited thefacility of the ten quadrillion speed computer “Kei.” There may be no spacefor keeping lions. (Author: Misawa)

Program of Winter School 2011
for the Integrated Simulation of Living Matter[Day 1] January 6 (Thursday)
13:15 - 13:45
13:45 - 15:15
15:15 - 16:15
16:15 - 17:15

17:15 - 19:15

19:15 - 19:30
19:30 - 24:00

Opening greeting
Koji Kaya (Program Director)
Future ISLiM
Ryutaro Himeno (Vice Program Director)[Day 2] January 7 (Friday)
8:00 - 9:00
9:00 - 10:15

Break and check-in

About the Gordon Bell Award
Yosuke Ohno (High-Performance Computing Team)
Hiroshi Koyama (High-Performance Computing Team)
Keigo Nitori (High-Performance Computing Team)
Study meeting on computational science for biology
Molecular dynamics –Chairperson : Miyashita (Molecular Scale Team)
Brain –
Chairperson : Urakubo (The University of Tokyo)
Blood flow –Chairperson : Nanasawa (Tokai University): Ishimine (Organ and Body Scale Team)
Genome –Chairperson : Misawa (Data Analysis Fusion Team)Break

Convivial party and night session
Poster presentation
Poster tour

10:15 - 10:30
10:30 - 11:00

11:00 - 11:30
11:30 - 12:00
12:30 - 13:30
13:30 - 14:30

Breakfast

Presentation of the study meeting on
computational science for biology
By the groups of molecular dynamics, brain,
blood flow and genome
Break

Coarse-grained biomolecular modeling andsimulation program CafeMol
Hiroo Kenzaki (Kyoto University School of Science)
Determination and comprehensive analysis of
genome sequences in Japanese subjects using
super parallel sequencer
kihiro Fujimoto (Center for Genomic Medicine, RIKEN)
General discussion
Closing greeting
Lunch

Visiting Advanced Institute for Computational
Science, RIKEN

BioSupercomputing Newsletter Vol.4 11

ISLiM Participating Institutions❶ Tohoku University❷ Japan Advanced Instituteof Science and Technology❸ RIKEN❹ The University of Tokyo❺ The Institute of Statistical Mathematics❻ Keio University❼ Chiba University❽ Tokyo Institute of Technology❾ Yokohama City University❷
 Tokai University
 Kyoto University
 Ritsumeikan University
 Osaka University
 Kobe University Hiroshima University


❶

❺

❸
❹
❻
❽
❾

❼





Event information▪Seminar held by Institute for Protein Research, Osaka University/(co-hosted by) BioSupercomputing Research Community●Date : March 4 (Friday): New Era of Biosimulations with Super Computers

March 5 (Saturday): Training session: Practice of molecular simulation and intracellular network analysis● Location : Seminar Room, 1st floor, main building of Institute for Protein Research, Osaka University (Suita Campus)
3-2, Yamadagaoka, Suita, Osaka, Japan 565-0871● Contact person: Haruki Nakamura (harukin@protein.osaka-u.ac.jp)

Event report▪Next-Generation Supercomputing Symposium 2010
and 1st Joint Workshop for 5 Strategic Programs
On January 17, 2011, the“Next-Generation Supercomputing Symposium 2010 and 1st Joint
Workshop for 5 Strategic Programs”was held on the Port Island, Kobe. The RIKEN Advanced
Institute for Computational Science, which operates the 10 quadrillion speed "K computer",and interested persons from 5 research fields doing research using the K computer, gathered
together for the first time. The symposium was highly successful, and there were about 300 participants. From the active
discussion, there was a feeling that this project is making a contribution to life and society due to collaboration between
the field of computational science and that of computer science to achieve new breakthroughs.

BioSupercomputing
Vol.4
Newsletter2011.2The “Next-Generation Integrated Simulation of Living Matter” is a projectsponsored by the Ministry of Education, Culture, Sports, Science and Technology,
in which research and development of simulation software to understand various
phenomena occurring in the biological systems, including molecules and thehuman body, have been undertaken to realize a petascale simulation by making
full use of the performance of a ten quadrillion speed computer known as “Kei.”

Computational Science Research Program,
RIKEN Research Cluster for Innovation

Issued : February 2011

2-1, Hirosawa, Wako, Saitama, 351-0198 Japan
TEL : +81-48-462-1488 FAX : +81-48-462-1220
http ://www.csrp.riken.jp