modeling in molecular biologypks/presentation/litschau-05.pdf · modeling in molecular biology...
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Modeling in Molecular Biology
Peter Schuster
Institut für Theoretische Chemie, Universität Wien, Austria, andThe Santa Fe Institute, Santa Fe, New Mexico, USA
Third GEN-AU Summer School: Ultra-Sensitive Proteomics and Genomics
Litschau, 29.– 31.08.2005
Web-Page for further information:
http://www.tbi.univie.ac.at/~pks
Mathematical modelsDiscrete methods Continuous methods
Enumeration, combinatorics Differentiation, IntegrationGraph theory, network theory OptimizationString matching (sequence comparison)
Dynamical systemsStochastic difference equs. Difference equs. Stochastic differential equs. Differential equs.
n , t dn , t n , dt dn , dt … ODE
n , x , t dn , x , t n , dx , dt dn , dx , dt … PDE
Simulation methodsCellular automata Genetic algorithms Neural networks Simulated annealing Differential equs.
Structure prediction and optimizationDiscrete states Continuous states
Dynamic programming Simplex methods Gradient techniques
RNA secondary structures, lattice proteins 3D-Structures of (bio)molecules
OCH2
OHO
O
PO
O
O
N1
OCH2
OHO
PO
O
O
N2
OCH2
OHO
PO
O
O
N3
OCH2
OHO
PO
O
O
N4
N A U G Ck = , , ,
3' - end
5' - end
Na
Na
Na
Na
5'-end 3’-endGCGGAU AUUCGCUUA AGUUGGGA G CUGAAGA AGGUC UUCGAUC A ACCAGCUC GAGC CCAGA UCUGG CUGUG CACAG
Definition of RNA structure
5'-End
5'-End
5'-End
3'-End
3'-End
3'-End
70
60
50
4030
20
10
GCGGAUUUAGCUCAGDDGGGAGAGCMCCAGACUGAAYAUCUGGAGMUCCUGUGTPCGAUCCACAGAAUUCGCACCASequence
Secondary structure
Symbolic notation
A symbolic notation of RNA secondary structure that is equivalent to the conventional graphs
RNA sequence
RNA structureof minimal free
energy
RNA folding:
Structural biology,spectroscopy of biomolecules, understanding
molecular functionEmpirical parameters
Biophysical chemistry: thermodynamics and
kinetics
Sequence, structure, and design
G
GG
G
GG
G GG
G
GG
G
GG
G
U
U
U
U
UU
U
U
U
UU
A
A
AA
AA
AA
A
A
A
A
UC
C
CC
C
C
C
C
C
CC
C
5’-end 3’-end
S1(h)
S9(h)
Free
ene
rgy
G
0
Minimum of free energy
Suboptimal conformations
S0(h)
S2(h)
S3(h)
S4(h)
S7(h)
S6(h)
S5(h)
S8(h)
The minimum free energy structures on a discrete space of conformations
RNA sequence
RNA structureof minimal free
energy
RNA folding:
Structural biology,spectroscopy of biomolecules, understanding
molecular function
Inverse FoldingAlgorithm
Iterative determinationof a sequence for the
given secondarystructure
Sequence, structure, and design
Inverse folding of RNA:
Biotechnology,design of biomolecules
with predefined structures and functions
The Vienna RNA-Package:
A library of routines for folding,inverse folding, sequence andstructure alignment, kinetic folding, cofolding, …
Minimum free energycriterion
Inverse folding of RNA secondary structures
1st2nd3rd trial4th5th
The inverse folding algorithm searches for sequences that form a given RNA secondary structure under the minimum free energy criterion.
Sk I. = ( )ψfk f Sk = ( )
Sequence space Structure space Real numbers
Mapping from sequence space into structure space and into function
Sk I. = ( )ψfk f Sk = ( )
Sequence space Structure space Real numbers
Sk I. = ( )ψ
Sequence space Structure space
Sk I. = ( )ψ
Sequence space Structure space
The pre-image of the structure Sk in sequence space is the neutral network Gk
AUCAAUCAG
GUCAAUCAC
GUCAAUCAUGUCAAUCAA
GUCAAUCCG
GUCAAUCG
G
GU
CA
AU
CU
G
GU
CA
AU
GA
G
GUC
AAUU
AG
GUCAAUAAGGUCAACCAG
GUCAAGCAG
GUCAAACAG
GUCACUCAG
GUCAGUCAG
GUCAUUCAGGUCCAUCAG GUCGAUCAG
GUCU
AUCA
G
GU
GA
AUC
AG
GU
UA
AU
CA
G
GU
AA
AU
CA
G
GCC
AAUC
AGGGCAAUCAG
GACAAUCAG
UUCAAUCAG
CUCAAUCAG
GUCAAUCAG
One-error neighborhood
The surrounding of GUCAAUCAG in sequence space
Degree of neutrality of neutral networks and the connectivity threshold
A multi-component neutral network formed by a rare structure: < cr
A connected neutral network formed by a common structure: > cr
Reference for postulation and in silico verification of neutral networks
Properties of RNA sequence to secondary structure mapping
1. More sequences than structures
Properties of RNA sequence to secondary structure mapping
1. More sequences than structures
Properties of RNA sequence to secondary structure mapping
1. More sequences than structures
2. Few common versus many rare structures
Properties of RNA sequence to secondary structure mapping
1. More sequences than structures
2. Few common versus many rare structures
n = 100, stem-loop structures
n = 30
RNA secondary structures and Zipf’s law
Properties of RNA sequence to secondary structure mapping
1. More sequences than structures
2. Few common versus many rare structures
3. Shape space covering of common structures
Properties of RNA sequence to secondary structure mapping
1. More sequences than structures
2. Few common versus many rare structures
3. Shape space covering of common structures
Properties of RNA sequence to secondary structure mapping
1. More sequences than structures
2. Few common versus many rare structures
3. Shape space covering of common structures
4. Neutral networks of common structures are connected
Properties of RNA sequence to secondary structure mapping
1. More sequences than structures
2. Few common versus many rare structures
3. Shape space covering of common structures
4. Neutral networks of common structures are connected
GkNeutral Network
Structure S k
Gk Ck
Compatible Set Ck
The compatible set Ck of a structure Sk consists of all sequences which form Sk as its minimum free energy structure (the neutral network Gk) or one of itssuboptimal structures.
Structure S 0
Structure S 1
The intersection of two compatible sets is always non empty: C0 C1
Reference for the definition of the intersection and the proof of the intersection theorem
A ribozyme switch
E.A.Schultes, D.B.Bartel, Science 289 (2000), 448-452
Two ribozymes of chain lengths n = 88 nucleotides: An artificial ligase (A) and a natural cleavage ribozyme of hepatitis- -virus (B)
The sequence at the intersection:
An RNA molecules which is 88 nucleotides long and can form both structures
Two neutral walks through sequence space with conservation of structure and catalytic activity
Cell biology
Regulation of cell cycle, metabolic networks, reaction
kinetics, homeostasis, ...
The bacterial cell as an example for the simplest form of autonomous life
The human body:
1014 cells = 1013 eukaryotic cells + 9 1013 bacterial (prokaryotic) cells,
and 200 eukaryotic cell types
Linear chain
Network
Processing of information in cascades and networks
Albert-László Barabási, Linked – The New Science of NetworksPerseus Publ., Cambridge, MA, 2002
••
Formation of a scale-free network through evolutionary point by point expansion: Step 000
••
Formation of a scale-free network through evolutionary point by point expansion: Step 001
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Formation of a scale-free network through evolutionary point by point expansion: Step 002
••
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Formation of a scale-free network through evolutionary point by point expansion: Step 003
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•
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Formation of a scale-free network through evolutionary point by point expansion: Step 004
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Formation of a scale-free network through evolutionary point by point expansion: Step 005
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Formation of a scale-free network through evolutionary point by point expansion: Step 006
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Formation of a scale-free network through evolutionary point by point expansion: Step 007
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Formation of a scale-free network through evolutionary point by point expansion: Step 008
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Formation of a scale-free network through evolutionary point by point expansion: Step 009
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Formation of a scale-free network through evolutionary point by point expansion: Step 010
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Formation of a scale-free network through evolutionary point by point expansion: Step 011
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Formation of a scale-free network through evolutionary point by point expansion: Step 012
••
•
•
•
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•
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•
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• •••
•
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Formation of a scale-free network through evolutionary point by point expansion: Step 024
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• 14
10
22
2
2
22
22
2
2
2
2
2 2
333
3
3
33
12
5
5
links # nodes
2 143 65 2
10 112 114 1
Analysis of nodes and links in a step by step evolved network
A B C D E F G H I J K L
1 Biochemical Pathways
2
3
4
5
6
7
8
9
10
The reaction network of cellular metabolism published by Boehringer-Ingelheim.
The citric acid or Krebs cycle (enlarged from previous slide).
General conditionsInitial conditions
: T , p , pH , I , ...:
... ... S , u
Boundary conditionsboundary normal unit vector
Dirichlet
Neumann
:
:
:
)0(x
),( trgx S =
Timet
Con
cent
ratio
n
( )x tSolution curves: xi(t)
Kinetic differential equations
);(2 kxfxDtx
+∇=∂∂
),,(;),,(;);( 11 mn kkkxxxkxftdxd
KK ===
Reaction diffusion equations
),(ˆ trgxuux S =∇⋅=
∂∂
Parameter setm,,2,1j;),I,Hp,p,T(j KK =k
The forward problem of chemical reaction kinetics (Level I)
General conditionsInitial conditions
: T , p , pH , I , ...:
... ... S , u
Boundary conditionsboundary normal unit vector
Dirichlet
Neumann
:
:
:
)0(x
),( trgx S =
Timet
Con
cent
ratio
n
( )x tSolution curves: xi(t)
Kinetic differential equations
);(2 kxfxDtx
+∇=∂∂
),,(;),,(;);( 11 mn kkkxxxkxftdxd
KK ===
Reaction diffusion equations
),(ˆ trgxuux S =∇⋅=
∂∂
Parameter setmjIHppTkj ,,2,1;),,,,;I( G KK =
Gen
ome:
Seq
uenc
e I G
The forward problem of cellular reaction kinetics (Level I)
The inverse problem of cellularreaction kinetics (Level I) Time
tCo
ncen
tratio
n
Data from measurements
(t ); = 1, 2, ... , x j Nj
xi (t )j
Kinetic differential equations
);(2 kxfxDtx
+∇=∂∂
),,(;),,(;);( 11 mn kkkxxxkxftdxd
KK ===
Reaction diffusion equations
General conditionsInitial conditions
: T , p , pH , I , ...:
... ... S , u
Boundary conditionsboundary normal unit vector
Dirichlet
Neumann
:
:
:
)0(x
),( trgx S =
),(ˆ trgxuux S =∇⋅=
∂∂
Parameter setmjIHppTk j ,,2,1;),,,,;I( G KK =
Gen
ome:
Seq
uenc
e I G
The forward problem of bifurcation analysis in cellular dynamics (Level II)
The inverse problem of bifurcationanalysis in cellular dynamics (Level II)
1 2 3 4 5 6 7 8 9 10 11 12
Regulatory protein or RNA
Enzyme
Metabolite
Regulatory gene
Structural gene
A model genome with 12 genes
Sketch of a genetic and metabolic network
Timet
Con
cent
ratio
n
xi (t)
Sequences
Vienna RNA Package
Structures and kinetic parameters
Stoichiometric equations
SBML – systems biology markup language
Kinetic differential equations
ODE Integration by means of CVODE
Solution curves
A + B X2 X Y
Y + X D
yxkd
yxkxky
yxkxkbakx
bakba
3
32
2
32
21
1
tdd
tdd
tdd
tdd
tdd
=
−=
−−=
−==
The elements of the simulation tool MiniCellSim
SBML: Bioinformatics 19:524-531, 2003; CVODE: Computers in Physics 10:138-143, 1996
ATGCCTTATACGGCAGTCAGGTGCACCATT...GGCTACGGAATATGCCGTCAGTCCACGTGGTAA...CCGDNA string genotype
environment
mRNA
Protein
RNA
Metabolism
RNA and proteinstructures
enzymes and smallmolecules
Recycling of moleculescell membrane
nutrition waste
genotype-p e h p mappinge ynot
genetic regulation network
metabolic reaction network
transport system
The regulatory logic of MiniCellSym
The model regulatory gene in MiniCellSim
The model structural gene in MiniCellSim
Neurobiology
Neural networks, collectiveproperties, nonlinear
dynamics, signalling, ...
A single neuron signaling to a muscle fiber
The human brain
1011 neurons connected by 1013 to 1014 synapses
BA
Christof Koch, Biophysics of Computation. Information Processing in single neurons. Oxford University Press, New York 1999.
Christof Koch, Biophysics of Computation. Information Processing in single neurons. Oxford University Press, New York 1999.
Christof Koch, Biophysics of Computation. Information Processing in single neurons. Oxford University Press, New York 1999.
Neurobiology
Neural networks, collectiveproperties, nonlinear
dynamics, signalling, ...
)()()(1 43llKKNaNa
M
VVgVVngVVhmgICtd
Vd−−−−−−=
mmdtdm
mm βα −−= )1(
hhdtdh
hh βα −−= )1(
nndtdn
nn βα −−= )1(
Hogdkin-Huxley OD equations
A single neuron signaling to a muscle fiber
Gating functions of the Hodgkin-Huxley equations
Temperature dependence of the Hodgkin-Huxley equations
)()()(1 43llKKNaNa
M
VVgVVngVVhmgICtd
Vd−−−−−−=
mmdtdm
mm βα −−= )1(
hhdtdh
hh βα −−= )1(
nndtdn
nn βα −−= )1(Hogdkin-Huxley OD equations
Hhsim.lnk
Simulation of space independent Hodgkin-Huxley equations:Voltage clamp and constant current
Hodgkin-Huxley partial differential equations (PDE)
nntn
hhth
mmtm
LrVVgVVngVVhmgtVC
xV
R
nn
hh
mm
llKKNaNa
β)1(α
β)1(α
β)1(α
2])()()([1 432
2
−−=∂∂
−−=∂∂
−−=∂∂
−+−+−+∂∂
=∂∂ π
Hodgkin-Huxley equations describing pulse propagation along nerve fibers
Hodgkin-Huxley ordinary differential equations (ODE)
Travelling pulse solution: V(x,t) = V( ) with
= x + tnnn
hhh
mmm
LrVVgVVngVVhmgVCVR
nn
hh
mm
llKKNaNaM
β)1(αθ
β)1(αθ
β)1(αθ
2])()()([θ1 432
2
−−=∂∂
−−=∂∂
−−=∂∂
−+−+−+∂∂
=∂∂
ξ
ξ
ξ
πξξ
Hodgkin-Huxley equations describing pulse propagation along nerve fibers
50
0
-50
100
1 2 3 4 5 6 [cm]
V [
mV
]
T = 18.5 C; θ = 1873.33 cm / sec
T = 18.5 C; θ = 1873.3324514717698 cm / sec
T = 18.5 C; θ = 1873.3324514717697 cm / sec
-10
0
10
20
30
40
V
[mV
]
6 8 10 12 14 16 18 [cm]
T = 18.5 C; θ = 544.070 cm / sec
T = 18.5 C; θ = 554.070286919319 cm/sec
T = 18.5 C; θ = 554.070286919320 cm/sec
Propagating wave solutions of the Hodgkin-Huxley equations
Hodgkin-Huxley ordinary differential equations (ODE)
Travelling pulse solution: V(x,t) = V( ) with
= x + t
nnn
mmm
LrVVgVVngVVnnhmgVCVR
nn
mm
llKKNaNaM
β)1(αθ
β)1(αθ
2])()()()([θ1 400
32
2
−−=∂∂
−−=∂∂
−+−+−−++∂∂
=∂∂
ξ
ξ
πξξ
)1(125.0)(exp125.0;αE
α 80800VV
nNa
nV
−≈−=+= β
An approximation to the Hodgkin-Huxley equations
Propagating wave solutions of approximations to the Hodgkin-Huxley equations
Evolutionary biology
Optimization through variation and selection, relation between genotype,
phenotype, and function, ...
Generation time
Selection and adaptation
10 000 generations
Genetic drift in small populations 106 generations
Genetic drift in large populations 107 generations
RNA molecules 10 sec 1 min
27.8 h = 1.16 d 6.94 d
115.7 d 1.90 a
3.17 a 19.01 a
Bacteria 20 min 10 h
138.9 d 11.40 a
38.03 a 1 140 a
380 a 11 408 a
Multicelluar organisms 10 d 20 a
274 a 200 000 a
27 380 a 2 × 107 a
273 800 a 2 × 108 a
Time scales of evolutionary change
Genotype = Genome
GGCUAUCGUACGUUUACCCAAAAAGUCUACGUUGGACCCAGGCAUUGGAC.......GMutation
Fitness in reproduction:
Number of genotypes in the next generation
Unfolding of the genotype:
RNA structure formation
Phenotype
Selection
Evolution of phenotypes
Ij
In
I2
Ii
I1 I j
I j
I j
I j
I j
I j +
+
+
+
+
(A) +
fj Qj1
fj Qj2
fj Qji
fj Qjj
fj Qjn
Q (1- ) ij-d(i,j) d(i,j) = lp p
p .......... Error rate per digit
d(i,j) .... Hamming distance between Ii and Ij
........... Chain length of the polynucleotidel
dx / dt = x - x
x
i j j i
j j
Σ
; Σ = 1 ;
f
f x
j
j j i
Φ
Φ = Σ
Qji
QijΣi = 1
[A] = a = constant
[Ii] = xi 0 ; i =1,2,...,n ;
Chemical kinetics of replication and mutation as parallel reactions
Mutation-selection equation: [Ii] = xi 0, fi > 0, Qij 0
Solutions are obtained after integrating factor transformation by means of an eigenvalue problem
fxfxnixxQfdtdx n
j jjn
i iijn
j jiji ====−= ∑∑∑ === 111
;1;,,2,1, φφ L
( ) ( ) ( )( ) ( )
)0()0(;,,2,1;exp0
exp01
1
1
0
1
0 ∑∑ ∑
∑=
=
−
=
−
= ==⋅⋅
⋅⋅=
n
i ikikn
j kkn
k jk
kkn
k iki xhcni
tc
tctx L
l
l
λ
λ
{ } { } { }njihHLnjiLnjiQfW ijijiji ,,2,1,;;,,2,1,;;,,2,1,; 1 LLlL ======÷ −
{ }1,,1,0;1 −==Λ=⋅⋅− nkLWL k Lλ
Formation of a quasispeciesin sequence space
Formation of a quasispeciesin sequence space
Formation of a quasispeciesin sequence space
Formation of a quasispeciesin sequence space
Uniform distribution in sequence space
Error rate p = 1-q0.00 0.05 0.10
Quasispecies Uniform distribution
Quasispecies as a function of the replication accuracy q
Chain length and error threshold
npn
pnp
pnpQ n
σ
σσσσ
ln:constant
ln:constant
ln)1(ln1)1(
max
max
≈
≈
−≥−⋅⇒≥⋅−=⋅
K
K
sequencemasterofysuperiorit
lengthchainrateerror
accuracynreplicatio)1(
K
K
K
K
∑ ≠
=
−=
mj j
m
n
ffσ
nppQ
Stock Solution Reaction Mixture
Replication rate constant:
fk = / [ + dS(k)]
dS(k) = dH(Sk,S )
Selection constraint:
# RNA molecules is controlled by the flow
NNtN ±≈)(
The flowreactor as a device for studies of evolution in vitro and in silico
Phenylalanyl-tRNA as target structure
Randomly chosen initial structure
f0 f
f1
f2
f3
f4
f6
f5f7
Replication rate constant:
fk = / [ + dS(k)]
dS(k) = dH(Sk,S )
Evaluation of RNA secondary structures yields replication rate constants
spaceSequence
Con
cent
ratio
n
Master sequence
Mutant cloud
“Off-the-cloud” mutations
The molecular quasispeciesin sequence space
S{ = ( )I{
f S{ {ƒ= ( )
S{
f{
I{M
utat
ion
Genotype-Phenotype Mapping
Evaluation of the
Phenotype
Q{jI1
I2
I3
I4 I5
In
Q
f1
f2
f3
f4 f5
fn
I1
I2
I3
I4
I5
I{
In+1
f1
f2
f3
f4
f5
f{
fn+1
Q
Evolutionary dynamics including molecular phenotypes
In silico optimization in the flow reactor: Evolutionary Trajectory
28 neutral point mutations during a long quasi-stationary epoch
Transition inducing point mutations change the molecular structure
Neutral point mutations leave the molecular structure unchanged
Neutral genotype evolution during phenotypic stasis
Evolutionary trajectory
Spreading of the population on neutral networks
Drift of the population center in sequence space
Spreading and evolution of a population on a neutral network: t = 150
Spreading and evolution of a population on a neutral network : t = 170
Spreading and evolution of a population on a neutral network : t = 200
Spreading and evolution of a population on a neutral network : t = 350
Spreading and evolution of a population on a neutral network : t = 500
Spreading and evolution of a population on a neutral network : t = 650
Spreading and evolution of a population on a neutral network : t = 820
Spreading and evolution of a population on a neutral network : t = 825
Spreading and evolution of a population on a neutral network : t = 830
Spreading and evolution of a population on a neutral network : t = 835
Spreading and evolution of a population on a neutral network : t = 840
Spreading and evolution of a population on a neutral network : t = 845
Spreading and evolution of a population on a neutral network : t = 850
Spreading and evolution of a population on a neutral network : t = 855
Evolutionary design of RNA molecules
D.B.Bartel, J.W.Szostak, In vitro selection of RNA molecules that bind specific ligands. Nature 346 (1990), 818-822
C.Tuerk, L.Gold, SELEX - Systematic evolution of ligands by exponential enrichment: RNA ligands to bacteriophage T4 DNA polymerase. Science 249 (1990), 505-510
D.P.Bartel, J.W.Szostak, Isolation of new ribozymes from a large pool of random sequences. Science 261 (1993), 1411-1418
R.D.Jenison, S.C.Gill, A.Pardi, B.Poliski, High-resolution molecular discrimination by RNA. Science 263 (1994), 1425-1429
Y. Wang, R.R.Rando, Specific binding of aminoglycoside antibiotics to RNA. Chemistry & Biology 2 (1995), 281-290
Jiang, A. K. Suri, R. Fiala, D. J. Patel, Saccharide-RNA recognition in an aminoglycoside antibiotic-RNA aptamer complex. Chemistry & Biology 4 (1997), 35-50
An example of ‘artificial selection’ with RNA molecules or ‘breeding’ of biomolecules
The SELEX technique for the evolutionary preparation of aptamers
Aptamer binding to aminoglycosid antibiotics: Structure of ligands
Y. Wang, R.R.Rando, Specific binding of aminoglycoside antibiotics to RNA. Chemistry & Biology 2(1995), 281-290
tobramycin
A
AA
AA C
C C CC
C
CC
G G G
G
G
G
G
G U U
U
U
U U5’-
3’-
AAAAA UUUUUU CCCCCCCCG GGGGGGG5’- -3’
RNA aptamer
Formation of secondary structure of the tobramycin binding RNA aptamer with KD = 9 nM
L. Jiang, A. K. Suri, R. Fiala, D. J. Patel, Saccharide-RNA recognition in an aminoglycoside antibiotic-RNA aptamer complex. Chemistry & Biology 4:35-50 (1997)
The three-dimensional structure of the tobramycin aptamer complex
L. Jiang, A. K. Suri, R. Fiala, D. J. Patel, Chemistry & Biology 4:35-50 (1997)
Acknowledgement of support
Fonds zur Förderung der wissenschaftlichen Forschung (FWF)Projects No. 09942, 10578, 11065, 13093
13887, and 14898
Wiener Wissenschafts-, Forschungs- und Technologiefonds (WWTF) Project No. Mat05
Jubiläumsfonds der Österreichischen NationalbankProject No. Nat-7813
European Commission: Contracts No. 98-0189, 12835 (NEST)
Austrian Genome Research Program – GEN-AU: BioinformaticsNetwork (BIN)
Österreichische Akademie der Wissenschaften
Siemens AG, Austria
Universität Wien and the Santa Fe Institute
Universität Wien
Coworkers
Peter Stadler, Bärbel M. Stadler, Universität Leipzig, GE
Paul E. Phillipson, University of Colorado at Boulder, CO
Heinz Engl, Philipp Kügler, James Lu, Stefan Müller, RICAM Linz, AT
Jord Nagel, Kees Pleij, Universiteit Leiden, NL
Walter Fontana, Harvard Medical School, MA
Christian Reidys, Christian Forst, Los Alamos National Laboratory, NM
Ulrike Göbel, Walter Grüner, Stefan Kopp, Jaqueline Weber, Institut für Molekulare Biotechnologie, Jena, GE
Ivo L.Hofacker, Christoph Flamm, Andreas Svrček-Seiler, Universität Wien, AT
Kurt Grünberger, Michael Kospach , Andreas Wernitznig, Stefanie Widder, Stefan Wuchty, Universität Wien, AT
Jan Cupal, Stefan Bernhart, Lukas Endler, Ulrike Langhammer, Rainer Machne, Ulrike Mückstein, Hakim Tafer, Thomas Taylor, Universität Wien, AT
Universität Wien
Web-Page for further information:
http://www.tbi.univie.ac.at/~pks