computaional prediction of protein structure,protein structure prediction,threding modelling detailed,drug discovery,mpharm,second semester,pharmacology

1. SUBMITTED TO :-
ASSOC PROF:- MR.PRAMODH KUMAR
DEPARTMENT OF PHARMACEUTICAL CHEMISTRY
SUBMITTED BY:- THEERTHA T
M-PHARM 1ST YEAR
SHREE DEVI COLLEGE OF PHARMACY

2. Protein three-dimensional structures are obtained
using two popular experimental techniques, x-ray
crystallography and nuclear magnetic resonance (NMR)
spectroscopy
. There are many important proteins for which the
sequence information is available, but their three
dimensional structures remain unknown.
Therefore, it is often necessary to obtain approximate
protein structures through computer modeling.

3. Computational prediction
Homology modeling Threading modeling ab initio
(knowledge based) (knowledge based) (stimulation)

6. Definition of fold recognition
• Given
1. A data base of given known 3D structure mapped
to a concise format (templates,folds)
2. A primary sequence of unknown tertiary structure
• Find
1. The data base structure with best global sequence-
structure alignment (threading)

7. Protein fold recognition
• Can be applied when homology modeling method
provide no reliable prediction
• Attempt to identify a model fold for a given target
sequence among the known folds even if no
sequence similarity can be detected

8. Protein threading also known as fold recognisation is a
method of protein modelling which is used to model
those protein which have the same fold as that of
known structure but do not have homologus protein
with known strucure
It differs from the homology modeling method of
structure prediction as it (protein threading) is used for
proteins which do not have their homologous protein
structures deposited in the Protein Data Bank (PDB),
whereas homology modeling is used for those proteins
which do.

9. Threading works by using statistical knowledge of
the relationship between the structures deposited in
the PDB and the sequence of the protein which one
wishes to model
Protein threading is based on two basic
observations:
1)that the number of different folds in nature is
fairly small (approximately 1300).
2)that 90% of the new structures submitted to the
PDB in the past three years have similar structural
folds to ones already in the PD

10. The algorithms can be classified into two categories,
1)pairwise energy based
2)profile based.
The pairwise energy –based method was originally referred
to threading
profile –base method was originally defined as fold
recognition

11. Method for threading model
A. The construction of a structure template database
B. The design of the scoring function
C. Threading alignment
D. Threading prediction

12. The construction of a structure template
database
1)Select protein structures from the protein structure
databases as structural templates.
2)This generally involves selecting protein structures from
databases such as PDBFSSP, SCOP, or CATH, after
removing protein structures with high sequence similarities.
PDB(Protein Data Bank)
FSSP(Families of structurally similar proteins database)
SCOP(The Structural Classification of Proteins database)

13. B. The design of the scoring function
1)Design a good scoring function to measure the fitness
between target sequences and templates based on the
knowledge of the known relationships between the
structures and the sequences.
2) A good scoring function should contain mutation
potential, environment fitness potential, pairwise potential,
secondary structure compatibilities, and gap penalties.
3)The quality of the energy function is closely related to
the prediction accuracy, especially the alignment accuracy

14. Threading alignment
Align the target sequence with each of the structure
templates by optimizing the designed scoring function.
This step is one of the major tasks of all threading-
based structure prediction programs that take into
account the pairwise contact potential; otherwise, a
dynamic programming algorithm can fulfill it.

15. Threading prediction
Select the threading alignment that is statistically most
probable as the threading prediction.
Then construct a structure model for the target by
placing the backbone atoms of the target sequence at their
aligned backbone positions of the selected structural
templat

17. Threading Comparison with homology modeling
a) Homology modeling and protein threading are both
template-based methods and there is no rigorous
boundary between them in terms of prediction
techniques.
b) But the protein structures of their targets are different.
c) Homology modeling is for those targets which have
homologous proteins with known structure
(usually/maybe of same family), while protein threading
is for those targets with only fold-level homology found.

18. REFERENCE
1. Jones DT. (1999) Protein secondary structure prediction based on
positionspecific scoring matrices. J Mol Biol 292: 195–202.
2. 2. Shi J, Blundell TL, Mizuguchi K. (2001) FUGUE: sequence-structure
homology recognition using environment-specific substitution tables
and structure dependent gap penalties. J Mol Biol 310: 243–257.
3. McGuffin LJ, Jones DT. (2003) Improvement of the GenTHREADER
method for genomic fold recognition. Bioinformatics 19: 874–881.
4. Jones DT, Bryson K, Coleman A, et al. (2005) Prediction of novel and
analogous folds using fragment assembly and fold recognition. Proteins
61(7): 143–151.