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Ab-initio protein structure prediction. Chen Keasar BGU. ?. Any educational usage of these slides is welcomed. Please acknowledge. [email protected]. The problem : Predict the three dimensional structure of a protein based on its sequence. ?. ?. ?. ?. ?. ?. - PowerPoint PPT Presentation
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Ab-initio protein structure prediction
?
Chen KeasarBGU
Any educational usage of these slides is welcomed.Please acknowledge. [email protected]
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The problem: Predict the three dimensional structureof a protein based on its sequence.
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??Chen KeasarBGU
How can we predict protein structures?
Are we lucky?
yes
A
V
C WK
A
GK
C
A C C W K A
V GKC
C
+
A
V
C WK
A
GK
C
C
homology
no
ab initio
a bit
fold recognition
Chen KeasarBGU
Why is ab-initio prediction hard?
Chen KeasarBGU
Ab-initio is hard, why do it?Wait until enough proteins are solved
and use homology modeling/fold-recognition
Chen KeasarBGU
Because it’s there
Chen KeasarBGU
• Because homology modeling tells us nothing about the physical nature of the protein folding and stability.
• Because ab-initio methods can augment fold-recognition and homology (refinement, large loops, side chains).
• Because of ORFans (orphan ORFs).
• Because it can ease experimental structure determination.
• Because prediction is the basis of design.
Chen KeasarBGU
ab-initio protein structure prediction
Simulation of the actual folding process
1. Build an accurate initial
model (including energy
and forces).
2. Accurately simulate the
dynamics of the system.
3. The native structure will
emerge.
44
Optimization problem
1. Define some initial model.
2. Define a function mapping
structures to numerical
values (the lower the better).
3. Solve the computational
problem of finding the
global minimum.
44 Chen Keasar
BGU
Simulating the actual folding process
dimer a CHOOH
Model I – quantum description of the system
Chen KeasarBGU
Model II
Semi-empirical energy functions – forcefields
Classic world no quantum effects (that is no chemistry). Parameterized to reproduce experimental results for small
molecules. Their use for proteins is an extrapolation. The basic element is an atom:
• Unbreakable.• Represented by the X,Y,Z coordinates of its center.• Its attributes (volume, charge, mass etc.) are the basic
parameters of the energy function.
Chen KeasarBGU
Chen Keasar
BGU
Chen Keasar
BGU
Chen Keasar
BGU
Chen Keasar
BGU
The good newsThe model is rather accurate and correctly describe many natural phenomena.
The bad news• Each time step is hard to compute.• An order of 1012 steps are needed to simulate protein folding.
Chen KeasarBGU
conformation
ener
gyAb-initio protein structure prediction as
an optimization problem
2. Solve the computational problem of finding an optimal structure.
3.
1. Define a function that map protein structures to some quality measure.
Chen KeasarBGU
A dream function Has a clear minimum in the native structure. Has a clear path towards the minimum. Global optimization algorithm should find the
native structure.
Chen KeasarBGU
An approximate function Easier to design and compute. Native structure not always the global minimum. Global optimization methods do not converge. Many
alternative models (decoys) should be generated.
Chen KeasarBGU
An approximate function Easier to design and compute. Native structure not always the global minimum. Global optimization methods do not converge. Many
alternative models (decoys) should be generated. No clear way of choosing among them.
Decoy set
Chen KeasarBGU
Energy functions: Typically include terms for hydrophobicity, hydrogen bonds etc. Typically based on the distribution of structural features (say
contacts between alanine residues and arginine residues) in the
PDB. The more frequent is the feature the lower is the energy
associated with it.
A small problems – these assumptions are wrong.
A brilliant solution – ignore it.
Assumptions: These features are independent. The proteins in the PDB are a
representative sample of conformation
space.
Chen KeasarBGU
diamondlattice
fine square lattice
fragments continuous
Some residues
Basic element
residue
heavy atom
atom
half a residue
Not really
Ab-initio
torsion angle lattice
electrons & protons
Hinds &Levitt
Skolnik2000
Skolnik1998
Scheraga1998
Baker(Rosetta)
Levitt &Keasar
AMBR ECEPCHARM OPLS
ENCAD GROMOS
Levitt1976
Osguthorpe
JonesPark &
Levitt
Chen KeasarBGU
diamondlattice
fine square lattice
fragments continuous
Some residues
Basic element
residue
extended atom
atom
half a residue
torsion angle lattice
electrons & protons
Hinds &Levitt
Chen KeasarBGU
diamondlattice
fine square lattice
fragments continuous
Some residues
Basic element
residue
extended atom
atom
half a residue
torsion angle lattice
electrons & protons
Park &Levitt
Chen KeasarBGU
diamondlattice
fine square lattice
fragments continuous
Some residues
Basic element
residue
extended atom
atom
half a residue
torsion angle lattice
electrons & protons
Skolnik2000
Chen KeasarBGU
diamondlattice
fine square lattice
fragments continuous
Some residues
Basic element
residue
extended atom
atom
half a residue
torsion angle lattice
electrons & protons
Scheraga1998
Chen KeasarBGU
diamondlattice
fine square lattice
fragments continuous
Some residues
Basic element
residue
extended atom
atom
half a residue
torsion angle lattice
electrons & protons
Hinds &Levitt
Skolnik2000
Skolnik1998
Scheraga1998
Baker(Rosetta)
Levitt,Keasar
AMBR ECEPCHARM OPLS
ENCAD GROMOS
Levitt1976
Osguthorpe
JonesPark &
Levitt
Chen KeasarBGU
Apparently the best current method
