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Protein Functions

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18 views28 pages

Protein Functions

Uploaded by

arubaghaffar123
Copyright
© © All Rights Reserved
We take content rights seriously. If you suspect this is your content, claim it here.
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Instructor:

INTRODUCTION Dr. Muhammad Jawad Khan


TO
BIOINFORMATICS Department of Biosciences, CUI
(BIO310) Email: [email protected]
PROTEIN FUNCTIONAL
ANALYSIS
INTRODUCTION TO BIOINFORMATICS
HOW TO INFER PROTEIN
FUNCTION
Wet-lab. Experiments

Deduction from sequence


Multiple sequence alignment – conservation patterns
Homology searching

Deduction from structure


Threading
Structure-structure comparison
Homology modelling
DEDUCTION FROM SEQUENCE

Homologous genes or proteins are derived from a common ancestral


sequence.

Homologous proteins within or among species are similar in sequence


and are likely, but not guaranteed to have a similar function.

Comparison of an un-annotated sequence to known homologous


sequences is therefore a good starting point for predicting function
DEDUCTION FROM STRUCTURE

Because 3D protein structure is generally more well conserved than


protein sequence
Structural similarity is a good indicator of similar function in two or more
proteins.

Many programs have been developed to screen an unknown protein


structure against the Protein Data Bank and report similar structures
STEP 1. LEARN WHAT YOU CAN GET
FROM THE PROTEIN SEQUENCE

Find it

Pay attention to the quality of the functional


annotation

Understand its 1-D structure – domain organization,


{signatures, fingerprints}
STEP 2. IS THERE A 3D STRUCTURE? IF YES,
THEN WHAT CAN YOU LEARN FROM THAT?

Find it
Understand it
Characterize it
Understand its function(s) – these follow a power
law at the fold level – some folds are promiscuous
(many functions) others are solitary or of unknown
function
Question: is structure the answer to functional
modeling?

Answer: partly - the number of unique protein


sequences still outnumbers the number of unique
structures by 100:1

Structural Genomics
/
Structure Prediction
STEP 3. WHAT CAN BE OBTAINED FROM
STRUCTURE WHEN YOU HAVE IT?

Examples of what can be learnt


STEP 4. PROTEINS DO NOT FUNCTION IN ISOLATION BUT ARE
PART OF COMPLEX INTERACTION NETWORKS

http://www.genome.jp/kegg/
WHY MODEL PROTEIN
FUNCTION

The rate of discovery of new proteins far outweighs our ability to


functionally characterize them

Functional discovery of new proteins has implications in:


Drug discovery
Understanding of biological processes
Identification of disease states and treatment regimes
PROTEIN FUNCTION CATEGORIES

Catalysis (enzymes)
Binding – transport (active/passive)
Protein-DNA/RNA binding (e.g. histones, transcription factors)
Protein-protein interactions Protein-fatty acid binding (e.g. apolipoproteins)
Protein – small molecules (drug interaction, structure decoding)

Structural component (e.g. g-crystallin)


Regulation
Signalling
Transcription regulation
Immune system
Motor proteins (actin/myosin)
MULTIPLE PROTEIN FUNCTIONS

Many proteins combine functions

For example, some immunoglobulin structures are


thought to have more than 100 different functions (and
active/binding sites)

Alternative splicing can generate (partially) alternative


structures
OVERVIEW OF PROTEIN FOLDING

Many experiments have shown that proteins can spontaneously fold from
an unfolded state to their folded native state.

This proves that the amino acid sequence contains enough information to
specify tertiary structure. Bonds within the peptide backbone seek out
different possible conformations as the final tertiary structure is achieved.

Folding tends to occur via successive conformational changes leading to


secondary and then tertiary structure elements. The native conformation
of a protein typically is its lowest free energy, and therefore, most stable
structure.
PROTEIN PROTEIN INTERACTIONS (PPI)

PPIs refer to intentional physical contacts established between


two or more proteins as a result of biochemical events and/or
electrostatic forces

Examples of protein–protein interactions


Signal transduction
Transport across membranes
Cell metabolism
Muscle contraction
TYPES OF PROTEIN–PROTEIN
INTERACTIONS
ON THE BASIS OF THEIR COMPOSITION

Homo-oligomers
Macromolecular complexes constituted by only
one type of protein subunit
Several enzymes, carrier proteins and
transcriptional regulatory factors carry out their
functions as homo-oligomers.

Example: PPIs in Muscle Contraction Homo-


oligomers complex
HETERO-OLIGOMERS

Distinct protein subunits interact in hetero-oligomers, which are


essential to control several cellular functions.
ON THE BASIS OF THEIR BONDING

Covalent :
Strongest association - disulphide bonds or electron sharing
- Post translational modifications

Non-covalent :
Established during transient interactions by the
combination of weaker bonds
Hydrogen bonds,
Ionic interactions,
Van der Waals forces
Hydrophobic bonds
ON THE BASIS OF THEIR DURATION OF
INTERACTION

Transient Interactions :
Interactions that last a short period of time
reversible manner
E.g., G protein-coupled receptors only transiently bind to G proteins when they are
activated by extracellular ligands

Stable Interactions:
Proteins - interact for a long time, taking part of permanent
complexes as subunits
-carry out Functional or Structural roles
PROTEIN DOMAINS

• Interactions only possible due to structural domains within the


proteins
A protein domain is a conserved part of a given protein
sequence and (tertiary) structure that can evolve, function, and
exist independently of the rest of the protein chain

• Proteins hold structural domains that allow their interaction


with and bind to specific sequences on other proteins
PPIS IDENTIFICATION METHODS
BIND
(BIOMOLECULAR INTERACTION NETWORK DATABASE)

• http://bind.ca
• A free, open-source database for archiving and exchanging
molecular assembly information.
• The database contains
- Interactions
- Molecular complexes
- Pathways
AN IMPORTANT APPLICATION OF PPI

Protein–protein interfaces are highly attractive targets for drug


discovery because they are involved in many disease pathways
where therapeutic intervention would bring widespread benefit.

Drug Designing

Docking
MAJOR APPLICATION: DESIGNING DRUGS

Understanding How Structures Bind Other Molecules


(Function)
Designing Inhibitors
Docking, Structure Modeling
MOLECULAR DOCKING

Molecular docking is a kind of bioinformatic modelling which involves the


interaction of two or more molecules to give the stable adduct. Depending upon
binding properties of ligand and target, it predicts the three-dimensional structure of
any complex.
MOLECULAR DOCKING

Given two biological molecules determine:

- Whether the two molecules “interact”


- If so, what is the orientation that maximizes the “interaction”
while minimizing the total “energy” of the complex

Goal: To be able to search a database of molecular structures and retrieve


all molecules that can interact with the query structure

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