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Transcript of Correlation of DNA structural features with internal dynamics and conformational flexibility H....
![Page 1: Correlation of DNA structural features with internal dynamics and conformational flexibility H. Peter Spielmann University of Kentucky Dept. of Molecular.](https://reader035.fdocuments.us/reader035/viewer/2022062321/56649efc5503460f94c0fdb4/html5/thumbnails/1.jpg)
Correlation of DNA structural features with internal
dynamics and conformational flexibility
H. Peter Spielmann
University of Kentucky
Dept. of Molecular and Cellular Biochemistry
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Molecular Structure From NMR
• Average inter-atomic distances measured for non-exchangeable hydrogens
Refined solution structure of self-complementary DNA molecule containing G-T mismatches
5’-CCATGCGTGG-3’3’-GGTGCGTACC-5’
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Dynamic Processes on the ps-ns Timescale
Deoxyribose Re-puckering
Phosphate BI - BII Exchange
Internal Vibrational Modes
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C2’-endo C3’-endo
• Also less well characterized motions• Bases also move, but less than backbone• Spontaneous base pair opening (“breathing”)• Rocking about the glycosidic linkage ()
What is DNA “Flexibility”
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Internal Vibrational Modes
Order Parameters (S2)
Methine 13C Relaxation
Modelfree Analysis
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Methine Carbons in DNA
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![Page 8: Correlation of DNA structural features with internal dynamics and conformational flexibility H. Peter Spielmann University of Kentucky Dept. of Molecular.](https://reader035.fdocuments.us/reader035/viewer/2022062321/56649efc5503460f94c0fdb4/html5/thumbnails/8.jpg)
How to Combine Disparate Dynamic Data to Obtain Information on Specific Motional Modes in DNA?
![Page 9: Correlation of DNA structural features with internal dynamics and conformational flexibility H. Peter Spielmann University of Kentucky Dept. of Molecular.](https://reader035.fdocuments.us/reader035/viewer/2022062321/56649efc5503460f94c0fdb4/html5/thumbnails/9.jpg)
Molecular Dynamics Simulation• Newtonian model of a quantized system
• Atomic positions/velocities change in femtosecond steps, based on current velocities and inter-nuclear interactions, dependent on force field equations:
• Parameterized to reproduce experimental measurements of gross structural features
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Time-Averaged Restraints
• Different than conventional restraints, in that deviations are allowed as long as the restraint is satisfied on average over a particular time frame (10-50 ps)
r (1/C) e( t t ) /
0
t
r( t ) i d t
1/ i
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Effects of Smoothing
= No smoothing
= 5 ps interval smoothing
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Computing Dynamics from MD
C(t)P2(( ) ( t)
r 3( )r 3( t)
C(t)S2 (1 Sf2 )e( t / f) (Sf
2 S2 )e( t / s )
C(t)S2 (1 S2 )e( t / e )
• Autocorrelation function:
• Lipari-Szabo modelfree formalism:
• Clore et al. extended model:
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0.75
0.8
0.85
0.9
0.95
1
0 500 1000
0.75
0.8
0.85
0.9
0.95
1
0 500 1000
Effect of Smoothing on T8:C1’C(t)
t (ps)
Data 2-parameter 4-parameter
C(t)
t (ps)
Before After
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Dynamics Correlations from NMR
• Correlations between S2, phosphate population, deoxyribose ring population, helical parameters
3’
5’
%BI vs. C1’5’ & %S5’
R2 = 0.79• Correlations not
evident in MD trajectories
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Dynamics Relate to Recognition
Flexibility DynamicsNMR& MDDeformability
Sequence(Damage?)
Specific
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Normal Mismatch
Biological Relevance
MutS:Mismatch
Recognition
Deformation:-Bend-Compressed, Deepened Major Groove-Widened Minor Groove
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C G GC A T G C T G
CGG CATGCTG
GT-2
GT-5
C G GC A C G C T G
CGG CACGCTG
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Normal vs. Mismatch
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Maj
or G
roov
e W
idth
(Å
)
8
10
12
14
16
18
20
C4/T4 G5 C6 G7
Min
or G
roov
e W
idth
(Å
)
4
5
6
7
8
9
10
C4/T4 G5 C6 G7
= Normal
= Mismatch
Groove Widths & Flexibility
Mismatched DNA has more flexibility inmajor groove width
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NH
HO
HO OH
NH
N
N
N
O
dR
1R-(-)-cis-anti-benzo[c]phenanthrene-N2-deoxyguanosine adduct
NH
HO
HO OH
NH
N
N
N
O
dR
1S-(+)-cis-anti-benzo[c]phenanthrene-N2-deoxyguanosine adduct
Diasteromeric carcinogen adducts
5’-CCATCGCTACC-3’3’-GGTAGCGATGG-5’
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Conclusions
• Mechanical coupling exists in DNA
• Structure and dynamics are related
• Time-averaged restrained MD simulations are more accurate than are unrestrained MD simulations
• Smoothing improves accuracy of tarMD
• tarMD can reveal dynamic features of biological relevance
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Acknowledgements
• Richard J. Isaacs
• William Rayens
• NSF
• Kentucky Center for Computational Sciences
• NCSA
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