nucleic acid structure prof. thomas e. cheatham iii
TRANSCRIPT
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nucleic acid structureProf. Thomas E. Cheatham III
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Where art thou nucleic acid?
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5’-GUCUGGCAUUGGGAUUCGGGUUUCUCAGAAACUUGGAUUUCUAACCUGAAAAAUCACUUUCGGGGACCGUGCUUGGC-3’
?
NH2+
NH2
NH
N
NH2+
NH2
NH
N
O
?
Our long-term goals are to enable the end-stage of nucleic acid structure refinement, to accurately model nucleic acid structure and dynamics, and to probe the interaction of molecules targeting RNA and DNA.
Given a putative RNA model can we refine it? Can we evaluate its relative importance? Can we probe the interaction with other molecules / drugs?
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N
NN
N
NH2
O
OHOH
HH
HH
OP-O
O-
O
Base
Sugar
Phosphate
A nucleotide has three parts:
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N
NN
N
NH2
O
OHOH
HH
HH
OP-O
O-
O
N
NN
N
NH2
O
HOH
HH
HH
OP-O
O-
O
Base
Sugar = ribose
Phosphate
Base
Sugar = deoxyribose
Phosphate
DNA and RNA have different sugars:
RNA
DNA
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The sugar-phosphate backbone
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thymineadenine
cytosineguanine
C4’
C3’
03’
PC5’
C4’
C2’ C3’
C1’N1C2
O2
N3
N4
N1O2
N3O4
N9N7
N3N2
N1
O2
N6N1
N3N9N7
O4’
O2’
AMBER names and atom types (parm94.dat)
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Various sugar ring puckering conformations. Those on the left are denoted S (forsouth); those on the right, N (for north). The C3 -endo conformation is seen at the ′top right, and the C2 -endo conformation at the ′ top left. The notation of E and T conformations is also given
Sugar puckering
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Sugar puckering
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Purines and pyrimidines
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The glycosidic torsion parameter
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Watson-Crick base pairing
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A-DNA and B-DNA form helices
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Base stacking
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Base pair and base pair step helicoidals
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Moving on to RNA
The two types of sugar pucker most commonly found in nucleic acids. TheC3 -endo pucker is prevalent in RNA and A-form DNA, whereas the C2 -endo pucker ′ ′is characteristic of B-form DNA. It is seen that the C3 -endo pucker produces a ′significantly shorter phosphate-phosphate distance in the backbone, resulting in a more compact helical conformation.
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RNA has more base pairing possibilities(DNA also has alternative base pairs)
Left: Canonical Watson–Crick GC base pair (cis). Right: GC reverse Watson–Crickbase pair (trans).
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Structures of base pairs involving at least two hydrogen bonds. The 28 possible base pairs that involve at least two hydrogen bonds as compiled by I. Tinoco Jr. Watson-Crick, Reverse Watson-Crick, Hoogsteen, Reverse Hoogsteen, Wobble, Reverse Wobble
The ten possible purine-pyrimidine base pairsThe seven possible homo purine-purine base pairs
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The four possible hetero purine-purine base pairs
The seven possible pyrimidine-pyrimidine base pairs
Ignacio Tinoco, Jr. in Gesteland, R. F. and Atkins, J. F. (1993) THE RNA WORLD. Cold Spring Harbor Laboratory Press.
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N
N
N
N
N
R
H
H
HH
N
N
NN
NR
H
H
H
H
N
NN
N
N
RH
H
H
HN
N
NN
N R
H
H
H
H
N
NN
N
N
R
H
H
HH
N
NN
NN
RH
H
H
H
N
NN
N N
R H
H
H
H
N
N
N
N
N
R
HH
H H
NN
N
N
N
R
H
HH
H N
N
NN
N
R
H
H
H
H
N
N
N
N
N
R
H
H
HH
N
N
N
N
N
R
H
H
H
H
N
N
NN
N
R
H
H
H
H
NN
N
NN
RH
HH
H
NN
N
NN
R
H
H H
HN
N
N
NN
RH
HH
H
N
N N
NN
RH
H
H
H NN
N
NN
RH
HH
H
NN
N
NN
RH
HH
H
N
N
NN
N R
H
H
H
H
cisWCWC cisHH cisWCSh
transWCH transHSh cisWCH(a)
cisWCH(b)transWCWC
transHH
transWCSh
Single H-bonded A-A base pairs
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RNA uses chemically modified bases
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conformational selectionvs.
induced fit
(in helix recognition)
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are the force fields reliable?(free energetics, sampling, dynamics)
en
erg
y
“reaction coordinate”
Computer power?
experimental
vs.
all tetraloopsNMR structuresof DNA & RNA
crystalsimulations
RNA motifsRNA-drug interactions
quadruplexes
What we typically find if we run long enough…
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100 independent simulations of 2KOC “UUCG” tetraloop
…longer runs…
Limited sampling & too complex:
Is there a simpler set of systems?
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Convergence as a function of time
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We can converge a tetranucleotide! How about a RNA tetraloop?
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Tutorial time!