Prof Thomas E Cheatham III Where art thou nucleic acid 5 G U C U GG C A UU GGG A UU C GGG UUU C U C A G AAA C UU GG A UUU C U AA CC U G AAAAA U C A C UUU ID: 461582
Download Presentation The PPT/PDF document "nucleic acid structure" is the property of its rightful owner. Permission is granted to download and print the materials on this web site for personal, non-commercial use only, and to display it on your personal computer provided you do not modify the materials and that you retain all copyright notices contained in the materials. By downloading content from our website, you accept the terms of this agreement.
Slide1
nucleic acid structure
Prof. Thomas E. Cheatham IIISlide2
Where art thou nucleic acid?Slide3
5
’-G
U
C
U
GG
C
AUUGGGAUUCGGGUUUCUCAGAAACUUGGAUUUCUAACCUGAAAAAUCACUUUCGGGGACCGUGCUUGGC-3’
?
?
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?Slide4
N
N
N
N
NH
2
O
OH
OH
H
H
H
H
O
P
-O
O-
O
Base
Sugar
Phosphate
A nucleotide has three parts:Slide5
N
N
N
N
NH
2
O
OH
OH
H
H
H
H
O
P
-O
O-
O
N
N
N
N
NH
2
O
H
OH
H
H
H
H
O
P
-O
O-
O
Base
Sugar = ribose
Phosphate
Base
Sugar = deoxyribose
Phosphate
DNA and RNA have different sugars:
RNA
DNASlide6
The sugar-phosphate backboneSlide7
thymine
adenine
cytosine
guanine
C4’
C3’
03’
PC5’C4’C2’C3’C1’N1C2O2N3N4
N1
O2
N3
O4N9
N7
N3
N2
N1
O2
N6
N1
N3
N9
N7
O4’
O2’
AMBER names and atom types (parm94.dat)Slide8
Various sugar ring puckering conformations. Those on the
left
are denoted S (for
south); 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 givenSugar puckeringSlide9
Sugar puckeringSlide10
Purines and pyrimidinesSlide11
The glycosidic torsion parameterSlide12
Watson-Crick base pairingSlide13
A-DNA and B-DNA form helicesSlide14
Base stackingSlide15
Base pair and base pair step
helicoidalsSlide16
Moving on to RNA
The two types of sugar pucker most commonly found in nucleic acids. The
C3′-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.Slide17
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).Slide18
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 WobbleThe ten possible purine-pyrimidine base pairsThe seven possible homo purine-purine base pairsSlide19
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. Slide20
cisWCWC
cisHH
cisWCSh
transWCH
transHSh
cisWCH(a)
cisWCH(b)
transWCWC
transHH
transWCSh
Single H-bonded A-A base pairsSlide21Slide22Slide23
RNA uses chemically modified basesSlide24
conformational selection
vs.
induced fit
(in helix recognition)Slide25
are the force fields reliable?
(free energetics, sampling, dynamics)
energy
“reaction coordinate”
Computer power?
experimental
vs.
a
ll
tetraloops
NMR structures
of DNA & RNA
crystal
simulations
RNA motifs
RNA-drug interactions
quadruplexes
What we typically find if we run long enough…Slide26
100 independent simulations of 2KOC “UUCG”
tetraloop
…longer runs…
Limited sampling & too complex:
Is there a simpler set of systems?Slide27
Convergence as a function of timeSlide28Slide29
We c
an
converge a
tetranucleotide
!
H
ow about a RNA tetraloop?Slide30Slide31Slide32Slide33Slide34Slide35Slide36Slide37
Tutorial time!