Protein dynamics

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Protein dynamics

• Folding/unfolding dynamics
• Passage over one or more energy barriers
• Transitions between infinitely many conformations
• Fluctuations near the folded state
• Local conformational changes
• Fluctuations near a global minimum

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Fluctuations near folded structure
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Center for Computational Biology and
Bioinformatics
Folding/unfolding energy landscapes
Thermodynamic equilibrium ? native state has
lowest free energy
Reference
B. Ozkan, K.A. Dill I. Bahar, Protein Sci. 11,
1958-1970, 2002.
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Knowledge-based studies Exploiting PDB
structures...
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http//www-fp.mcs.anl.gov/gaasterland/sg-review-s
lides.html
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• Protein folding problem
• Predicting 3-dimensional structure from amino
  acid sequence
• A unique folded structure (native conformation,
  native fold) is assumed by a given sequence,
  although infinitely many conformations can be
  accessed.
• Which? (Protein folding problem)
• How, why? (Folding kinetics)

Basic postulate Thermodynamic equilibrium ?
Global energy minimum
CASP (Critical Assessment of Structure Prediction)
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Protein structure prediction

• Three computational methods
• Homology modeling
• Threading
• Ab initio simulations

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Homology/comparative modeling
MODELLER is used for homology or comparative
modeling of protein three-dimensional structures
(1). The user provides an alignment of a sequence
to be modeled with known related structures and
MODELLER automatically calculates a model
containing all non-hydrogen atoms. MODELLER
implements comparative protein structure modeling
by satisfaction of spatial restraints (2, 3), and
can perform many additional tasks, including de
novo modeling of loops in protein structures,
optimization of various models of protein
structure with respect to a flexibly defined
objective function, multiple alignment of protein
sequences and/or structures, clustering,
searching of sequence databases, comparison of
protein structures, etc. MODELLER is written in
Fortran 90 and runs on the Pentium PC's (Linux
and Win XP), Apple Macintosh (OS X) and
workstations from Silicon Graphics (IRIX), Sun
(Solaris), IBM (AIX), and DEC Alpha (OSF/1).
(A. Sali)
http//guitar.rockefeller.edu/modeller/modeller.ht
ml
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                   SWISS-MODEL
An Automated Comparative Protein Modelling
Server accessible via the ExPASy (Expert Protein
Analysis System) web server (by Peitsch et al.)
STEPS 1. Search for suitable templates
(from ExNRL-3D , using BLAST) 2. Check sequence
identity with target (SIM will select all
templates with sequence identities above 25 and
Ngt 20) 3. Create ProModII jobs 4. Generate
models (ProModII) using known 3-d templates 5.
Energy minimization with Gromos96
http//swissmodel.expasy.org/SWISS-MODEL.html
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Predict Protein (Rost)
http//www.embl-heidelberg.de/predictprotein/
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Structural Homology

• Dali Server (Sander-Holm)
• http//www2.ebi.ac.uk/dali/

L. Holm and C. Sander (1996) Mapping the protein
universe. Science 273595-602.
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Threading (Fold recognition)
Loopp (Elber) Threader (Jones)
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Ab initio simulations

• Protarch (Scheragas group)
• Rosetta (Bakers lab)
• Touchstone (Skolnick)

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Need for Low Resolution Approaches
Coarse-grained Models with Empirical Force
Fields are the most tractable - if not the only
possible computational tools for investigating
large systems, and complex biological processes
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Virtual bond model

• Single interaction site per residue, identified
  by the a- or b-carbon
• Need for empirical potentials for inter-residue
  interactions

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Swiss-PdbViewer Free, powerful and easy to
use Program Download http//us.expasy.org/spdbv
/mainpage.htm Manual Download http//us.expasy.o
rg/spdbv/program/DeepViewManual.pdf Sample Files
Download 1A30, 1A8G from PDB
bank http//www.rcsb.org/pdb/
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Tutorial pages http//us.expasy.org/spdbv/text/tu
torial.htm http//www.usm.maine.edu/7Erhodes/SPVT
ut/index.html 1. Load a file pop up functional
Windows and panels Make sure you activate control
panel, alignment windows every time you load a
file 2. Selection, Display, Color Practice a.
Mark all the lysine in chain A red in Ribbon
diagram b. Color all the alpha-helix by their
solvent accessibility c. Color all the non-polar
residues by their Temp-B factor 3. Handy icons
move all or move selection Common used
functions measure atom-atom distance mutate a
residue Use Esc when you want to jump out a
certain function!
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4. Computing tools H-bond Surface Energy Energy
minimization 5. Structure alignment (Fit) Switch
between active layers Visible check box, move
check box 6. Homology Modeling (SWISS MODEL) 7.
Output Save as Fig, Save the modified layer 8.
Script commands running script Have fun. Play
around with it! Contact Lee lwy1_at_pitt.edu at
CCBB