©2001 Werner G. Krebs. All Rights Reserved. http://bioinfo.mbb.yale.edu/~wkrebs
the macromolecular
motions database:
a standardized system for analyzing
and visualizing macromolecular
motions in a database framework
werner g. krebs
Gerstein Lab/Molecular
Biophysics & Biochemistry
Yale University
I. Motions and Civilization: James
Watt & the two-stroke engine
James Watt’s (1736-1819) most important improvement to the
reciprocating steam engine (1769 patent) was the use of the
double-action principle. In this system, the steam is used first on
one side of the piston, then on the other.
Source: http://cougar.slvhs.slv.k12.ca.us/~pboomer/physicstextbook/ch9.html

Source: http://www.cchem.berkeley.edu/~shkgrp/people/boisvert/thesis/ch2.html
GroEL
GroEL motion: “GroEL as a twostroke engine”
Image Credits: http://www.protein.bio.msu.su/biokhimiya/contents/v63/full/63040444.htm
©2001 Werner G. Krebs. All Rights Reserved. http://bioinfo.mbb.yale.edu/~wkrebs
GroEL
Molecular Mechanism of Hebb Learning?
If two
Source:
http://www.ysbl.york.ac.uk/~bar
ton/picture/cam/cam002.html
of neural network
learning:
Mechanical
Function
interconnected
neurons are
frequently
activated together,
the strength of the
connection between
them should be
Calmodulin
Engineering
Equivalent
CampK2 Actin
No
Complete
Structure
Moves and
relaxes in
response to
calcium levels
Autophosphorylation
sensor
Memory
Device
switch
memory
involves a hinge
motion
Motion
tenses
synapse
distance
Motor
Analogue or
Digital Integrator
(capacitor, storage
tank, mechanical
counter, flip-flop)
increased.

Image Credit:
http://www.ks.uiuc.edu/Research/cell_motility/actin
/
Hebb rule
Complex
Component


©2001 Werner G. Krebs. All Rights Reserved. http://bioinfo.mbb.yale.edu/~wkrebs
Interpolation Engine 1:
Adiabatic Mapping with a patched XPLOR



The molecule is deformed in a series
of small steps. (For the server, we
divided the distance between starting
and ending positions into an equal
number of steps)
Energy minimization is performed
after each step to produce structures
with comparable energies.
Problems arise for large deformations
if the energy minimization methods
cannot effectively remove the
accumulated stresses
©2001 Werner G. Krebs. All Rights Reserved. http://bioinfo.mbb.yale.edu/~wkrebs
movie in science
Volkman, B.,
Lipson, D.,
Wemmer, D. and
Kern, D. "Twostate allosteric
behavior in a
single-domain
signaling protein"
(2001) Science.
Published in
March 23
Science.
30S ribosome RNA motion


Recently modified
morph server software
to analyze nucleic acid
motions.
Completed custom
morph of 30S subunit
of ribosome for V
Ramakrishnan, J Ogle
et al.
queue_manager
©2001 Werner G. Krebs. All Rights Reserved http://bioinfo.mbb.yale.edu/~wkrebs
Protein Morpher in Action
©2001 Werner G. Krebs. All Rights Reserved. http://bioinfo.mbb.yale.edu/~wkrebs
 “Some months ago I had
Testimonials 0
submitted the coordinates of our
glycerol kinase structure which
revealed substantial domain
, the
manuscript is
heading to
Biochemistry and
motion…
Well
I'd like to include a
web address pointing
to the morphed
GK movie on
your server … for
the reviewers to look
at…. Many thanks!”
-- Dr. Cory Edward Bystrom, Ph.D.
(via email)
Formerly,
Institute of Molecular Biology
University of Oregon
Presently,
Senior Research Scientist
New Zealand Diary Research Institute
“I
really
like the
motions
database
….”
Testimonials I
-- Prof. Helen M. Berman, Ph.D. (in person)
Professor of Chemistry
Adjunct Professor, Biological Chemistry
President, American Crystallographic Association, (1989-90).
Director,
RCSB Protein Data Bank
Rutgers University
New Brunswick, N.J

“I think your
Testimonials II
morphing
server would
be a
fabulous
way to get a feeling for the
difference between two structures
when RMS isn't
useful. By making a movie, someone
could see the ways in which two structures
are similar or different. Have you used it for
this purpose? This is what we wanted to do
by submitting two structures to it. We have
docked two tRNA structures in two different
ways and wanted to "animate" the difference
between the two dockings. Thanks, Russ.
”
--
Russ B. Altman, MD, PhD (via email)
Associate Professor of Medicine
(and Computer Science, by courtesy)
Director, Biomedical Informatics Training Program
Associate Director, Stanford Medical Scientist Training Program
Thrust Leader, Molecular Science at NPACI/SDSC
President, International Society for Computational Biology
Stanford Medical Informatics
Stanford University Medical Center
251 Campus Drive, MSOB X-215
Stanford, Ca 94305-5479
you
are the
master,
 “Werner,
Testimonials III
it looks so
cool! My
colleagues flip
out about
this….
Thanks again and I
hope we can keep in touch, I have more
stuff about moving proteins coming.
”
-- Prof. Dorothee Kern, Ph.D. (via email)
Assistant Professor of Biochemistry
Dept. of Biochemistry, MS 009
Brandeis University
Waltham, MA 02454-9110, USA
Press Testimonials



Mentioned in NetWatch column, s.v.
“Protein Shake” in Science (1999)
284(7), p. 871.
It was also noted by the HMS
Beagle Biological Web Magazine as
a “Web Pick”.
It is mentioned in Philip E Bourne,
Judith Murray-Rust, Jeremy H
Lakey Current Opinion in Structural
Biology 1999, 9:9-10.
How we add value
Database of Macromolecular Motions
230
200
automatically found in PDB
manually curated from
literature
user-submitted
Motions in PDB
db
3800
Database as fraction of all motions
(not to scale)

What are they?

Proteins, Nucleic Acids
(Hammerhead)

Sidechains (trivial),
Loops (LDH), Domains
(ADK), Subunits (Hb)
When a Ligand Binds:
Open, Closed
Essential link between
structure and function
 catalysis,
regulation, transport,
formation of
assemblies,
and cellular locomotion
A complicated biological
phenomena that can be
studied in quantitative detail
 changes in thousands of
atomic coordinates



macromolecular motions
information, size, then
packing based classification
Calmodulin
Snapshot of welcome screen
Snapshot of motion entry
HIV Reverse Transcriptase
N umb er
K no wn
F or ms
Size
of
Motio n
Mechani sm
of
Examp les
Motio n
#
H in ge
TIM, LDH , TGL14
F ragm ent Shear
Insulin
3
U nc las sif iableMS2 C oat
3
D om ain
Subunit
Allosteric
PFK, H b, GP
N on-allos teric Ig VL-VH
U nc las sif iable
Motion
2 f orm s
H in ge
LF, AD K, C M 16
Shear
C S, TrpR , AAT 8
R ef old
Serpin, R T
3
Special
Ig elbow
1
U nc las sif iableTBP, EF -tu
3
H in ge
F ragm ent Shear
U nc las sif iablebR
1 f orm
4
2
1
D om ain
R ef old
H in ge
LF~TF ,SBP
10
Shear
H K~PGK,H SP 4
Special
U nc las sif iableMy osin
4
Subunit
Allosteric
N on-allos teric
U nc las sif iablePCN A, GroEL
3
information,
size, then
packing based
classification
Citrate Synthase
How we add value
Database of Macromolecular Motions
230
200
automatically found in PDB
manually curated from
literature
user-submitted
Motions in PDB
db
3800
Database as fraction of all motions
(not to scale)
How we add value II
Notably
Motionless
1%
Database of Macromolecular Motions
230
Unclassifiable
20%
200
automatically found in PDB
manually curated from
literature
Hinge
45%
Other/NonAllosteric
7%
user-submitted
Allosteric
7%
3800
Partial
Refolding
4%
Nucleic
Acid
2%
Shear
14%
©2001 Werner G. Krebs. All Rights Reserved. http://bioinfo.mbb.yale.edu/~wkrebs
mechanisms of motions by
packing
 Packing classification is
Notably
Motionless
1%
dominated by
Unclassifiable
20%
Hinge (45%)
 Unclassifiable (20%)
 Shear (14%)

categories
Hinge
45%
Other/NonAllosteric
7%
Allosteric
7%
Partial
Refolding
4%
Nucleic
Acid
2%
Shear
14%
©2001 Werner G. Krebs. All Rights Reserved. http://bioinfo.mbb.yale.edu/~wkrebs
mechanisms of motions
by size
Complex
5%
Subunit
11%
Fragment
22%
Domain
62%
fragment motions better studied
fragment motions
(93% known)
are better studied than
domain motions
(72% known)
 most likely explanation:
experimentalists better
able to study smaller
motions
©2001 Werner G. Krebs. All Rights Reserved. http://bioinfo.mbb.yale.edu/~wkrebs

Suspected
7%
Fragment
Suspected
28%
Domain
Known
72%
Known
93%
percent studied by technique
Other
CD
©2001 Werner G. Krebs. All Rights Reserved. http://bioinfo.mbb.yale.edu/~wkrebs
TRX
MD
NMR






X-ray
NMR
MD
TR X-ray
CD
Other
95%
7%
3%
2%
2%
1%
X-ray
Studied
Not-studied
Experimental Methods
and Simulations
Users
Sequence/Structure Alignment
©2001 Werner G. Krebs. All Rights Reserved. http://bioinfo.mbb.yale.edu/~wkrebs
Modified Sieve-Fit Superposition
Screw-Axis Orientation
Homogenization
Database Information
Interpolation
Visual Rendering
Web Report
©2001 Werner G. Krebs. All Rights Reserved. http://bioinfo.mbb.yale.edu/~wkrebs
alcohol dehydrogenase
©2001 Werner G. Krebs. All Rights Reserved. http://bioinfo.mbb.yale.edu/~wkrebs
diphtheria toxin (DT)
Impossible
morph;
example of
domain
swapping.
Not a true
motion.
©2001 Werner G. Krebs. All Rights Reserved. http://bioinfo.mbb.yale.edu/~wkrebs
conclusions

Macromolecular Database useful tool for obtaining information on protein and
nucleic acid motions

Integrated morph server actually a software suite that
homogenizes, interpolates, visualizes, and
analyzes protein and nucleic acid motions and
stores results in database

Morph server can handle loosely related protein structures, so useful as a tool
for evolutionary morphs as well as protein motions

Macromolecular Motions Database amendable to
statistical analysis and automatic data-mining
techniques

Data integrated into Partslist Database (http:/www.partslist.org)

Remains a fertile area of research
acknowledgements

Prof. Mark Gerstein

Dr. Vadim Alexandrov
Nat Echols
Dr. Yuval Kluger
Dr. Jiang Qian
Cyrus Wilson
Hiyuan Yu
Ronald Jansen & Jochen Junker






Rest of Gerstein Lab
 Research committee:

Prof. Dieter Soll
 Prof. Jennifer Doudna
Rest of MB&B Faculty


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