Mesoscopic Modeling of RNA Structure and Dynamics
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Transcript of Mesoscopic Modeling of RNA Structure and Dynamics
Mesoscopic Modeling of RNA Structure and Dynamics
Hin Hark Gan
A. Fundamentals of RNA structure1. Hierarchical folding2. Folding timescales
B. Issues in RNA modeling1. Mesoscopic models of RNA structure2. RNA energy function3. Ribosome modeling
NSF Goal: Transformative Research
Research that has the capacity to:Research that has the capacity to:(1) revolutionize existing fields, (1) revolutionize existing fields, (2) create new subfields, (2) create new subfields, (3) cause paradigm shifts, (3) cause paradigm shifts, (4) support discovery, and (4) support discovery, and (5) lead to radically new technologies.(5) lead to radically new technologies.
National Science BoardNational Science Board
A1. Hierarchical folding2D structure folds independently of the 3D structure
Explains mostof RNA fold’s free energy
Brion & Westhof1997
A2. Folding timescales
Thirumalai et al 2001
10s (2D)
1-10ms
50ms-100s
2D and 3D structures have distinct folding timescales.
Goal:Predict 3D structure and dynamics frominput 2D fold.
B1. Mesoscopic Models: RNA Stems
?
beads
Perfect stems
Imperfect stems
Small bulge in stems ?
- Unpaired bases are important for tertiary interactions- How to effectively model unpaired bases in helices?
Similar to DNA modeling
Can DNA elastic models be applied to RNA?• Elastic constants: stretching (h), bending (g),
twisting (C)
• Applicable to long perfect helices (typically, <10 basepairs)
• Imperfect helices require special considerations (e.g., varying elastic potentials and interactions)
• Not applicable to single strand regions
(h,g,C) (h,g,C) EE
(h’,g’,C’)(h’,g’,C’) E’ E’
- Varying constants and interactions
Mesoscopic Models: Single strands• Use existing coarse-grained
models
• Baker group: 1-bead model (considers only base, neglect sugar and phosphate, base centroid as the bead origin)
• Amaral group: bead-pin model
Overall mesoscopic RNA model is a mixture of elastic chain for helical segments and bead-pin model for unpaired bases.
B2. RNA Energy Function
Total energy= (H-H) + (H-S) + (S-S)
= (coaxial) + (A-minor) + (ribose zipper) + (pseudoknots) + …+ (Excluded volume) + (Van der Waals)+ (Electrostatics) + …
- Tertiary motif interactions (similar to -, -, etc. interactions for proteins)- Special importance of tertiary motifs for structure and dynamics?- Parameters: , , , , ,… ,…
S – single strand regionH – helical region
Tertiary motifterms
usual terms
Tertiary Interaction NetworksRecurrent Structural Motifs are Key to 3D folds
H: helix (ds)S: single strand (ss)
By Laing, XinS/S
tRNA D-loop:T-loop
Kissing hairpin
Pseudoknots
Chang & Tinoco 1994, Ennifar et al. 2001
Shen & Tinoco 1995 Van Batenburg et al.
2001
2 hairpinsSelf-comp., often 6 nt
2 intertwining regions Comp. bps
D/T loop interaction
Holbrook et al. 1978 Holbrook and Kim 1979
H/H
Coaxial helices
Junction, “pseudo-stem”A (in helix bridge)
Kim et al. 1974Cate et al. 1996
S/H
Ribose zipper
Antip. stem/loop interaction5′-CC-3′ (Stem)3′-AA-5′ (Loop) Cate et al. 1996Tamura & Holbrook 2002
A-minor motif
Clustering of A G-C preferred
Nissen et al. 2001
Tetraloop receptor
Tetraloop/internal loop5′- GAAA -3′5′-CC-UAAG-3′
Pley et al. 1994Cate et al. 1996
Butcher et al. 1997
Derivation and Optimization of Energy Function
• Structure data -> statistical potential, Eik ~ln(Pik )
• Thermodynamic data – denaturation curves from temperature and pH changes
• Other RNA data sources (e.g., decoy structures)
Brion & Westhof, 1997
B3. Modeling the Ribosome (NDPA proposal)
Goal: Model ribosome structure and dynamics usingmesoscopic models for all RNA and protein components and their interactions. Steitz group, Science 2000
RNA components
proteins
Impact on RNA Folding and Design
• Folding of larger RNAs (100-500 nt)
• Millisecond folding times
• RNA design aided by predicted 3D folds
• Ribosome dynamics and antibiotic action
Likely Yes/No
Probable Yes/No
Likely Yes
May be Yes
Likelihood Transformativeof success Research?Challenges