Protein Structure Prediction using Coarse Grain Force Fields · Nasir Mahmood. 12.02.2010. Protein...
Transcript of Protein Structure Prediction using Coarse Grain Force Fields · Nasir Mahmood. 12.02.2010. Protein...
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Nasir Mahmood
12.02.2010
Protein Structure Prediction using Coarse Grain Force Fields
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• Introduction
• Probabilistic Ab Initio – Standard– Score function– Search Method– Results
• Probabilistic Ab Initio - Extended– Score Function : Introducing Solvation– Search Method: Bias Fix– Results
• Outlook
• Summary
Overview
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“All the information required by protein to adopt its final conformation is encoded in its sequence”
Christian B. Anfinsen (1916 - 1995)
Source: http://nobelprize.org/
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• information he referred to has not been decoded yet
• interestingly, these days we also know about proteins like ‘prions’
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ExperimentalMethods
X-Ray Crystallography
NMRSpectroscopy
Cryo-EM
Time (year)
N
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More than 3 decades and only 60000+ structures
ExperimentalMethods
X-Ray Crystallography
NMRSpectroscopy
Cryo-EM
Time (year)
N
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Time (year)
N
610100×
61090×
61080×
61070×
61060×
61050×
61040×
61030×
61020×
61010×
SequenceDatabase Growth
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ExperimentalMethods
X-Ray Crystallography
NMRSpectroscopy
Cryo-EM
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Methods
ExperimentalMethods
X-Ray Crystallography
NMRSpectroscopy
Cryo-EM
Computational Methods
Homology Modeling
FoldRecognition
Ab Initio Modeling
PDB
Accu
racy
Computation cost
PDB
dep
ende
nce
Physical Principles
Experimental Data
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• Physics-based• Best but most difficult (Force fields)• Computationally expensive
• Statistics-based• Boltzmann distributions• Statistical mechanical ensembles
• We use Descriptive Statistics• Bayesian formulation• No hidden approximations• No energies but find distributions
• Monte Carlo Methods
• Molecular Dynamics
Ab Initio Methods
TE/k-i e B∆=P
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• Purely Probabilistic Force Field• Mixture of Probabilities:• Sequence, Structure, Solvation
• No energies• No Boltzmann statistics
• Coarse Grained • reduced dimensionality• relies on dihedral angles• no side chains• 5-atoms representation• Fragment Assembly
• Simulated Annealing / Monte Carlo• Move set: biased & unbiased• Acceptance criterion: ratio
of probabilities
Our Ab Initio Method
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ProbabilisticScore Function
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•Representation : • Reduced, Simplified• 5-atoms per amino acid• dihedral angles (phi, psi)
•Bivariate Gaussian
2. Structure
•Multi-way Bernoulli1. SequenceS A E M P
WN
FYK HQ
T SG
DIL C
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(A)
i
i + 1
i + 2
(B)Sequence Structure
P L E N R R V 3.11.1
2.00.9
1.5-2.5
1.72.3
-2.0-0.9
-1.5-1.2
-1.2-0.8
i
i + 1
i + 2
N
(C)
A S T C W R I -3.1-1.1
-2.0-0.9
-0.5-0.7
-1.7-0.5
-2.0-0.3
-1.5-0.8
-2.2-1.0
MS T C W R I -1.1-1.1
-2.0-0.9
-0.5-0.7
-1.7-0.5
-2.0-0.3
-1.5-0.8
-2.2-1.0
MT C W R I -1.1-1.1
-2.1-0.4
-0.5-0.7
-1.7-0.5
-2.0-0.3
-1.5-0.8
-2.2-1.0
F……
6101.5×
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ExpectationMaximization
Fragment Library
BayesianClassifier
GGGG ..GAEG ..GAEG ..DCWF ..WFDC ..
STDC ..STST..WFTG ..CCAD ..ACAD ..
Classified
Statistical Models
Fragment Generation
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Sequence
A S L T 2087
05-71
-3215
80-07
Structure
AS
LT
208705-71
-3215
80-07
SL
TM
208705-71
-3215
80-07
LT
LT
208705-71
-3215
80-07
TL
TI
208705-71
-3215
80-07
LT
TA
208705-71
-3215
80-07
TT
AT
208705-71
-3215
80-07
TA
QW
208705-71
-3215
80-07
AQ
WW
208705-71
-3215
80-07
QW
WE
208705-71
-3215
80-07
WW
EW
208705-71
-3215
80-07
WE
WC
208705-71
-3215
80-07
class 0class 1class 2
class 5
class 3class 4
class 6Classified
GGGG ..
GAEG ..
GAEG ..
DCWF ..
WFDC ..
STDC ..
STST..
WFTG ..
CCAD ..
ACAD ..
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Search Method
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Prob
abili
ty
Conformational space
Final Model
(i-1)
(i)
Relative probabilities:
• Normal methods :
( )( )1-i
ii xp
xp=PInitial (random)
conformation
TE/k-i e B∆=P
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73167 543117793 1466
psiphi
Random Angle Generator
0-180
180
0
180
phi
psi
-180
180
-180 180
0
0
PDB
FragmentLibrary fragments
Unbiased Biased
6102×≈
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Interplay of Cartesian Coordinates & Dihedral Angles
Choi, V.: 2005, On Updating torsion angles of molecular conformations, J Chem Inf Model 46, 438–444.
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Results
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NativeModel
Results
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2hfq
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NativeModel
Results
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2hd3
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NativeModel
Results
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Phi
Psi
2gzv
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Model
Results
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Time
Scor
e
2hj1
Native
Temperature
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Results
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Time
Scor
e
Phi
Psi
Temperature
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Score Function:Introducing Solvation
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PDB
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Trp
Gly Lys Ser
PDB
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• Representation : • Reduced, Simplified• 5-atoms per amino acid• dihedral angles (phi, psi)
• Bivariate Gaussian
2. Structure
• Multi-way Bernoulli
1. Sequence
S A E MPW
NFY
K HQ T SG DI L C
• Simple Gaussian
3. Solvation
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• Mixture Models: Connections Residues Geometry Location in protein
ExpectationMaximization
Fragment Library
BayesianClassifier
GGGG ..GAEG ..GAEG ..DCWF ..WFDC ..
STDC ..STST..WFTG ..CCAD ..ACAD ..
Re-Classified
Statistical Models
PDB
Sequence StructureA S L T -3.1
-1.1-2.0-0.9
-0.5-0.7
-1.7-0.5 12 07 08 11
Solvation
S L T I -2.0-0.9
-0.5-0.7
-1.7-0.5
-1.2-0.4 07 08 11 09
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Search Method:Bias Fix & Combining
Fragments
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Bias Fix
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Combining Fragments andProbabilities
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Results
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Native Model
1fsv
2hep
Results
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2k4x
1agt
Results
Native Model36
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2k53
2k4n
Native Model
Results
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Results
Native Model
2hf1
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Future Outlook
Hydrogen bond energy(kcal/mol)
• Introduce hydrogen bonds – as a probabilistic term
• Hydrogen bond energies have normal distribution
• Use Simple Gaussian model
N
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Summary
•Purely Probabilistic Approach for Protein Structure Prediction
• Score function consists of a set of probability distributions•Conformation probabilities - mixture of probabilities, no
energies at all
• generates protein/protein-like conformations• long-range interactions not well represented• In future, hydrogen bond term could improve results
• Application to sequence optimization•Rapid sampling – combine with other score functions
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Thanks for your attention!