DNA: Structure, Dynamics and Recognition

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DNA Structure, Dynamics and Recognition
L3 DNA dynamics
Les Houches 2004
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STRUCTURAL DATABASES
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RSCB-PDB
http//www.rscb.org
H.M. Berman, J. Westbrook, Z. Feng, G.
Gilliland, T.N. Bhat, H. Weissig, I.N.
Shindyalov, P.E. Bourne Nucleic Acids Research,
28 pp. 235-242 (2000)
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RSCB
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Full search
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Custom forms
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An example - chymotrypsin
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Display
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PDB file header
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NDB -http//ndbserver.rutgers.edu/
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NDB - atlas
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NDB - atlas
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CCDC - 1965
http//www.ccdc.cam.ac.uk/
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CSD small molecules
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CCDC products
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TRANSFAC - http//www.gene-regulation.com/
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HELICAL PARAMETERS
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Helical symmetry

• move between residues by translation along and
• rotation around the helical axis

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Finding a helical axis
(2) Find plane defined by vectors placed at origin
(1) Build vectors between helically
equivalent atoms
(3) Draw perpendiculars to chords between heads
of vectors
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Curved helical axis ?
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Cambridge convention
3
5
5
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Dickerson et al. J. Mol. Biol. 205, 1989, 787
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Helical parameters
Translation
Rotation
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Helicoidal parameters
Local
Global
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Extreme global solutions
Keep linear helical axis
Keep monomer orientations
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CURVES
R. Lavery and H. Sklenar J. Biomol. Struct. Dyn.
6, 1989, 655
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Base reference system
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Axis reference system
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Curves function
A) Bases (X, E) in the same place with respect
to the local axis (U, P) ?   A1) Rotation S
(Ui.Xi - Ui-1.Xi-1)2 - where X J, K, L   A2)
Translation S (Pi - Ei).Xi - (Pi-1 -
Ei-1).Xi-1)2   B) Axis straight and continuous
?   B1) Rotation S (Ui - Ui-1)2   B2)
Translation S (Qi - Qi-1)2 - where Qi (Pi -
Pi-1) - ltUgt.ltUgt.(Pi - Pi-1)   Final formula
F (X,Y,I,T) 10 (A1 B1) (A2 B2)
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Curves helical axis
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Helical parametersfor B- and A-DNA
Parameter B-DNA A-DNA Xdisp 0.0 -5.28 Y
disp 0.0 0.0 Inclination 1.5 20.7  Propeller -13.3
-7.5 G-Slide 0.0 0.0 G-Rise 3.38 2.56 G-Roll 0.0
0.0 G-Twist 36.0 32.7   L-Slide 0.08 -1.92 L-Rise
3.38 3.44 L-Roll 0.9 11.4 L-Twist 35.6 30.7   Pha
se 155 18 Amplitude 40 42
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B-DNA structural variation
Hartmann and Lavery Q. Rev. Biophys. 29, 1996, 309
Value Min. Max. Mean Value Min. Max. Mean
Xdisp -0.6 1.5 0.5 Shift -1.1 1.1 0.0
Inc 11 11 -1 Slide -1.1 1.1 -0.1
Tip -11 11 0 Rise 3.2 4.0 3.4
Buck -11 16 1 Tilt -8 8 0
Prop -24 5 -11 Roll -12 16 2
Open -8 8 1 Twist 22 51 36
a -109 -23 -64 d 90 173 132
b 112 -159 166 e 141 -61 -179
g -16 104 50 z 148 -68 -94
Pha 19 206 150 c -62 -160 -104
Amp 15 58 39
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B-DNA - 2ns dynamic trajectory
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"LONG" MD SIMULATIONS
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Molecular dynamics
Time integration of Newton's equation of
motion F ma -dE/dr m dr2/dt2 Taylor
expansion r(t dt) r(t) dt dr(t)/dt dt2/2
d2r(t)/dt2 Fastest movements O(10-15 s)
r
t
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Periodic boundary conditions
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Equilibration
Temp (K)
Equilibrate
Production
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NPT ensemble
Reassign or rescale velocities
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Heat
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Initially constrain solute
0
Minimize
Time (ns)
1
2
3
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MD snapshots
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MD time series- sugar phase- groove width
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MD time series- base pair Hbonds
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Ascona B-DNA Consortium
F. Lankas, Herovsky Inst. Czech Republic ?
EPFL R. Lavery, IBPC France J. Maddocks,
EPFL Switzerland H. Sklenar, MDC Germany
D. Beveridge, Wesleyan U. D. Case, Scripps
Institute T. Cheatham, U. Utah R. Osman, Mount
Sinai, NY M. Young, Berkeley
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136 unique tetramers
AAAA AAAC AAAG AAAT AAGA AAGC AAGG AAGT AATA AATC
AATG AATT ACGA ACGC ACGG ACGT AGAA AGAC AGAG AGAT
AGCA AGCC AGCG AGCT AGGA AGGC AGGG AGGT AGTA AGTC
AGTG AGTT ATAA ATAC ATAG ATAT ATGA ATGC ATGG ATGT
CAAA CAAC CAAG CAAT CAGA CAGC CAGG CAGT CATA CATG
CCGA CCGG CGAA CGAC CGAG CGAT CGCA CGCG CGGA CGGC
CGGG CGGT CGTA CGTC CGTG CGTT CTAA CTAG CTGA CTGC
CTGG CTGT GAAA GAAC GAAG GAAT GAGA GAGC GAGG GAGT
GATA GATC GATG GCGA GCGC GCGG GGAA GGAC GGAG GGAT
GGCA GGCC GGCC GGGA GGGC GGGG GGGT GGTA GGTC GGTG
GGTT GTAA GTAC GTAG GTGA GTGC GTGG GTGT TAAA TAAC
TAAG TAAT TAGA TAGC TAGG TAGT TATA TCGA TGAA TGAC
TGAG TGAT TGCA TGGA TGGC TGGG TGGT TGTA TGTC TGTG
TGTT TTAA TTGA TTGC TTGG TTGT
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ABC oligomers - construction
G-D-ABCD-ABCD-ABCD-G

• 15 base pairs
• Central tetranucleotide repeats
• GC terminal base pairs for stability
• No sampling for ilt3 or igt13
• Two copies of each tetranucleotide

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39 oligomer database
GGGGGGGGGGGGG AAAAAAAAAAAAA CGCGCGCGCGCGC TATATATA
TATAT AGAGAGAGAGAGA TGTGTGTGTGTGT AGGGAGGGAGGGA CG
GGCGGGCGGGC TGGGTGGGTGGGT GAAAGAAAGAAAG CAAACAAACA
AAC TAAATAAATAAAT CGGCCGGCCGGCC AGGAAGGAAGGAA TGGT
TGGTTGGTT TAATTAATTAATT CGGACGGACGGAC AGGCAGGCAGGC
A AGGTAGGTAGGTA TGGATGGATGGAT CGGTCGGTCGGTC TGGCTG
GCTGGCT CAAGCAAGCAAGC GAACGAACGAACG TAACTAACTAACT
CAATCAATCAATC TAAGTAAGTAAGT GAATGAATGAATG TGAGTGAG
TGAGT CGAGCGAGCGAGC TGCGTGCGTGCGT TAGATAGATAGAT GA
CAGACAGACAG TACATACATACAT AGCTAGCTAGCTA TGCATGCATG
CAT CGATCGATCGATC TGACTGACTGACT CGTACGTACGTAC
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Simulation protocol

• AMBER program
• PARM94 parameters
• Truncated octahedral box (7600 waters)
• Neutralising K counterions
• Particle Mesh Ewald electrostatics
• 2 fs timestep (SHAKE on X-H)
• Careful equilibration, NVT?NPT
• Save configuration every 1ps
• 15 ns trajectories (for Phase I)

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ABC dataset Phase I ? Finished 5/03

• 150 months of CPU time
• 0.6 ms of simulation
• (2.2x Vilin folding simulation)
• 600,000 coordinate sets
• 272 tetranucleotide steps
• 400 Gb of data

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ACGT trajectory
B-DNA A-DNA Last ns
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Helical parameters
Translation
Rotation
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ACGT helical parameters - instantaneous
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SYMMETRY?
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Each oligomer contains 2 "identical" tetramers
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ACGT helical parameters - histograms
C6pG7 C10pG11
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GCGC helical parameters - histograms
C4pG5 C6pG7 C8pG9 C10pG11
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GCGC helical parameters
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Backbone torsion angles

• d C5 C4 C3 O3
• O5 C5 C4 C3
• b P O5 C5 C4
• a O3 P O5 C5
• z C3 O3 P O5
• e C4 C3 O3 P

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CGCG backbone parameters
G7pC8 G11pC12
C6pG7 C10pG11
g-/g
g/t
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ag transition
a - G11pC12 g - G11pC12
g-
t
g
g
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ag impact on twist
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SEQUENCE DEPENDENT STRUCTURE?
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CpG translational parameters
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CpG rotational parameters
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IONS AROUND DNA
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Diffusion coefficients(10-9 m2sec-1 )
lt(xi(t0dt)-xi(t0))2gt 6D dt
K D 2.85 Exp1.96
lt(xi(t0dt)-xi(t0))2gt
Na D 1.72 Exp1.33
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Volume sampled by ions during 50ns simulation time
K
Na
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Most frequently visited zones
K
Na
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Tight binding
phosphate 2 2 3 2 2 9 5 3 13 2 3
strand 1 C1 C2 A3 T4 G5 C6 G7 C8 T9 G10 A11 C12
groove 1 3 7 12 2 1 5
groove 2 1 2 1 3 8 8,1 6 3
strand 2 G24 G23 T22 A21 C20 G19 C18 G17 A16 C15 T14 G13
phosphate 2 6 3 17 2 4 12 3 8 3 2
Na
phosphate 1 2 2 3 2 5 2 4 3 2 3
strand 1 C1 C2 A3 T4 G5 C6 G7 C8 T9 G10 A11 C12
groove 1 2 7 4 13,3 2 1
groove 2 2 2 1,1 1 3,8 3 11 1,6 1,1 1 2
strand 2 G24 G23 T22 A21 C20 G19 C18 G17 A16 C15 T14 G13
phosphate 2 3 2 3 2 4 3 3 6 1 1
K
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Minor groove width at C8 level
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a/g transitions in Na dynamics
red g green a
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a/g transitions in K dynamics
red g green a