Protein Structure Prediction

and Classification
Bioinformatics In Support Of
Proteomic Research

Dr.J.Vardhana
Assistant Professor, Dept of Biotechnology
VISTAS
Introduction
⚫ Protein structure prediction is the prediction of
the three-dimensional structure of a protein from
its amino acid sequence — that is, the prediction
of its folding and its secondary, tertiary, and
quaternary structure from its primary structure.
⚫ Structure prediction is fundamentally different
from the inverse problem of protein design.
Protein structure prediction is one of the most
important goals pursued by bioinformatics and
theoretical chemistry; it is highly important in
medicine (for example, in drug design) and
biotechnology (for example, in the design of
novel enzymes).
Methods
⚫ There are three major theoretical
methods for predicting the structure of
proteins:
⚫ Homology Modelling or Comparative
Modelling
⚫ Fold Recognition or Threading
⚫ Ab Initio Prediction.
Comparative Modelling
⚫ Comparative modelling exploits the fact that
evolutionarily related proteins with similar sequences,
as measured by the percentage of identical residues at
each position based on an optimal structural
superposition, have similar structures.
⚫ The similarity of structures is very high in the
so-called ``core regions'', which typically are
comprised of a framework of secondary structure
elements such as alpha-helices and beta-sheets.
⚫ Loop regions connect these secondary structures and
generally vary even in pairs of homologous structures
with a high degree of sequence similarity.
Fold Recognition Or “Threading"
⚫ Threading uses a database of known
three-dimensional structures to match sequences
without known structure with protein folds.
⚫ This is accomplished by the aid of a scoring
function that assesses the fit of a sequence to a
given fold.
⚫ These functions are usually derived from a
database of known structures and generally
include a pairwise atom contact and solvation
terms.
⚫ Threading methods compare a target sequence
against a library of structural templates,
producing a list of scores.
Fold Recognition Or "Threading"
⚫ The scores are then ranked and the fold with the
best score is assumed to be the one adopted by
the sequence.
⚫ The methods to fit a sequence against a library of
folds can be extremely elaborate
computationally, such as those involving double
dynamic programming, dynamic programming
with frozen approximation, Gibbs Sampling using
a database of ``threading'' cores, and branch and
bound heuristics, or as ``simple'' as using
sophisticated sequence alignment methods such
as Hidden Markov Models.
Ab Initio Prediction
⚫ The ab initio approach is a mixture of
science and engineering.
⚫ The science is in understanding how the
three-dimensional structure of proteins is
attained.
⚫ The engineering portion is in deducing
the three-dimensional structure given the
sequence.
Ab Initio Prediction
⚫ The biggest challenge with regards to the folding
problem is with regards to ab initio prediction,
which can be broken down into two
components: devising a scoring function that can
distinguish between correct (native or native-like)
structures from incorrect (non-native) ones, and
a search method to explore the conformational
space.
⚫ In many ab initio methods, the two components
are coupled together such that a search function
drives, and is driven by, the scoring function to
find native-like structures.
Protein Structure Prediction Software
⚫ A great number of structure prediction software
are developed for dedicated protein features and
particularity, such as disorder
prediction, dynamics prediction, structure
conservation prediction, etc.
⚫ Approaches include homology modeling, protein
threading, ab initio methods, secondary structure
prediction, and transmembrane helix and signal
peptide prediction.
⚫ Choosing the right method always begins by
using the primary sequence of the unknown
protein and searching the protein database.
Secondary Structure Prediction Tools
⚫ These tools predict local secondary
structures based only on the amino acid
sequence of the protein.
⚫ Predicted structures are then compared to
the DSSP score, which is calculated based on
the crystallographic structure of the protein
(more on the DSSP score here).
⚫ Prediction methods for secondary structure
mainly rely on databases of known protein
structures and modern machine learning
methods such as neural nets and support
vector machines.
Tertiary structure
⚫ All the information about a protein’s tertiary
structure is encoded in its primary structure (that is,
its amino acid sequence).
⚫ However, an enormous number of them can be
predicted, among which only one has the minimal free
energy and stability required to be folded properly.
⚫ Ab initio protein structure prediction thus requires
vast amount of computational power and time to
solve the native conformation of a protein, and
remains one of the top challenges for modern science.
⚫ Most popular servers include Robetta (using the
Rosetta software
package), SWISS-MODEL, PEPstr, QUARK.
Tertiary structure
⚫ If a protein of known tertiary structure shares at
least 30% of its sequence with a potential
homolog of undetermined structure, comparative
methods that overlay the putative unknown
structure with the known can be utilized to
predict the likely structure of the unknown.
⚫ Homology modeling and protein threading are
two main strategies that use prior information on
other similar protein to propose a prediction of
an unknown protein, based on its sequence.
⚫ Homology modeling and protein threading
software
include RaptorX, FoldX, HHpred, I-TASSER, and
more.
Conclusion
⚫ Proteomics methods are essential for studying protein
expression, activity, regulation and modifications.
⚫ Bioinformatics is an integral part of proteomics
research.
⚫ The recent developments and applications in proteomics
are discussed including mass spectrometry data analysis
and interpretation, analysis and storage of the gel images
to databases, gel comparison, and advanced methods to
study e.g. protein co-expression, protein–protein
interactions, as well as metabolic and cellular pathways.
⚫ The significance of informatics in proteomics will
gradually increase because of the advent of
high-throughput methods relying on powerful data
analysis.