Structural bioinformatics - bioinformatics03

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2 Οκτ 2013 (πριν από 3 χρόνια και 10 μήνες)

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STRUCTURAL
BIOINFORMATICS

Predicting Protein structure

What is Structural Bioinformatics?


is
the branch of

bioinformatics

which is related to
the analysis and prediction of the three
-
dimensional
structure of biological

macromolecules

such
as

proteins,

RNA, and

DNA.


It
deals with generalizations about macromolecular
3
D structure such as comparisons of overall folds
and local motifs, principles of molecular folding,
evolution, and binding interactions, and
structure/function relationships,

Structural bioinformatics

vs.

bioinformatics


DNA
mapping


DNA
and protein
sequence


Development
of
algorithms
for data
mining


Determine of
3
D
structures
in
biomolecules


Analysis
and
comparison
of
biomolecular

structures


Prediction
of
biomolecular

structure.


Bioinformatics

Structural bioinformatics

Experimental techniques for
structure determination


X
-
ray Crystallography


Nuclear Magnetic Resonance spectroscopy (NMR)


Prediction

Question?


Why is structure prediction is hard..?


Structure Prediction Approaches

1.
Homology (Comparative) Modeling

Based on sequence similarity with a protein for

which a structure has been solved.


2.

Threading (Fold Recognition)

Requires a structure similar to a known structure


3.
Ab
-
initio

fold prediction

Not based on similarity to a sequence
\
structure

Ab
-
initio fold prediction



Given only the sequence, try to predict the
structure based on
physico
-
chemical properties
(energy,
hydrophobicity

etc.)


Fold Recognition

(Threading)


Given a sequence and a library of folds, thread the
sequence through each fold. Take the one with the
highest score.


Homology Modeling


Basic
Idea

Triophospate ismoerases

44.7
% sequence identity

0.95
RMSD


1.
A protein structure is defined by its
amino acid sequence.


2.
Closely related sequences adopt
highly similar structures, distantly
related sequences may still fold into
similar structures.


3.
Three
-
dimensional structure of


proteins from the same family is


more conserved than their


primary sequences.


General Scheme

1.
Searching for structures related to the query sequence


2.
Selecting templates


3.
Aligning query sequence with template structures


4.
Building a model for the query using information from the
template structures


5.
Evaluating the model


Fiser A et al. Methods in Enzymology
374
:
461
-
491
(
2004
)

General Scheme

1
. Searching For Structures


How to select the right template?



Close subfamily
-

phylogenetic

tree



“Environment” similarity



Two ways to combine multiple templates:




Global model



alignment with different domain of the
target with little overlap between them





Local model



alignment with the same part of the target






More than one template


3
. Aligning



All comparative modeling programs depend on a
target
-
template alignment.


When the sequence similarity between the template
and target proteins is high, simple
pairwise

alignments are usually fine (e.g. Needleman
-
Wunsch

global alignment).


But some times blast is required.



Sequence alignment algorithms



Examples: the two most used in homology modeling are:



BLAST: General strategy is to optimize the maximal segment
pair (MSP) score
-

BLAST computes similarity, not alignment



FastA

(local alignment): searches for both full and partial
sequence matches, i.e., local similarity obtained; more
sensitive than BLAST, but slower; many gaps may represent
a problem


Building the model

5
. Model Evaluation


The accuracy of the model depends on its sequence
identity with the template:





Summary

Any Questions ?

Thank you