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nucleic acid structure - PowerPoint Presentation

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nucleic acid structure - PPT Presentation

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

rna base sugar dna base rna dna sugar pairs phosphate

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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 pairsSlide21
Slide22
Slide23

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 timeSlide28
Slide29

We c

an

converge a

tetranucleotide

!

H

ow about a RNA tetraloop?Slide30
Slide31
Slide32
Slide33
Slide34
Slide35
Slide36
Slide37

Tutorial time!