The mechanism of protein folding

S.Prasanth Kumar, S.Prasanth Kumar, BioinformaticianBioinformatician

Proteomics

The Mechanism of Protein FoldingThe Mechanism of Protein Folding

S.Prasanth Kumar Dept. of Bioinformatics Applied Botany Centre (ABC) Gujarat University, Ahmedabad, INDIA

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Alignment scoring schemesProtein folding

Physical process by which a polypeptide folds into its characteristic and functional three-dimensional structure

Folded proteins

Hydrophobic core -> side chain packing stabilizes the folded state

Charged or polar side chains occupies the solvent-exposed surface ->interact with surrounding water

Alignment scoring schemes

Important driving force in the folding process:

Minimize the number of hydrophobic side-chains exposed to solvent

Formation of intramolecular hydrogen bonds

Protein Stability:

Protein folding

Strength of hydrogen bonds depends on their environment

H-bonds in a hydrophobic core contribute more than H-bonds exposed to the aqueous environment to the stability of the native state

Alignment scoring schemesClassical Models

If folding is driven by local interactions, secondary structureformation precedes collapse

Alignment scoring schemesClassical Models

If folding is driven by nonlocal interactions, collapsed rives concurrent secondary structure formation

Alignment scoring schemesPerturbed Model

Energies of (HH, PP,HP) contacts are (-1, 0,0)

Contacts (AA, BB, AB) have energies (-3, -3, -1)

Native structures of HP models have hydrophobic cores, whereas the perturbed homopolymer model tend to separate into two sides with different monomer types

hydrophobic

polar

Alignment scoring schemesSidechain Model

Linear chain latticemodel (LCM) to represent the main chain (A)

A sidechain model (SCM)is created by attaching a single sidechain unit to each main-chain monomer

To represent side-chain rotameric DOF, each sidechain unit has the freedom to occupy any one empty lattice site

Alignment scoring schemesMolecular Chaperons

Specialized proteins called chaperones assist in the folding of other proteins

Alignment scoring schemesMolecular Chaperons

A well studied example is the bacterial GroEL system, assists in the folding of globular proteins. In eukaryotic organisms chaperones are known as heat shock proteins (HSP)

Most globular proteins are able to assume their native state unassisted

Chaperone-assisted folding is required in the crowded intracellular environment to prevent aggregation

Used to prevent misfolding and aggregation which may occur as a consequence of exposure to heat or other changes in the cellular environment

Alignment scoring schemes

The molecular surface of the immunodominant heat-shock chaperonin-10 of mycobacterium leprae

Molecular Chaperons

Alignment scoring schemesTransitioning to the Native State

Establishment of regular secondary and supersecondary structures, particularly alpha helices and beta sheets, and afterwards tertiary structure

Amino acid sequence

Formation of quaternary structure usually involves the "assembly" or "coassembly" of subunits that have already folded

The regular alpha helix and beta sheet structures fold rapidly because they are stabilized by intramolecular hydrogen bonds

Alignment scoring schemesTransitioning to the Native State

Finally, energetically favorable native conformation,.

Folding may involve covalent bonding in the form of (disulfide bridges) and/or the formation of metal clusters

Pass through an intermediate "molten globule" state

Alignment scoring schemesLevinthal Paradox

Total number of possible conformations of a polypeptide chain is large

Takes an astronomical length of time to find correct structure by means of a systematic search of all conformational space

Recent experimental and theoretical studies suggest no such apparent paradox

Stochastic Approach

Folding process does not involve a series of mandatory steps between specific partially folded states, but rather a stochastic search of the many conformations accessible to a polypeptide chain

Alignment scoring schemesStochastic Search

Conformational space accessible to the polypeptide chain is reduced as the native state is approached

Inherent fluctuations in the conformation of an incompletelyfolded polypeptide chain enable even residues at very differentpositions in the amino acid sequence to come into contact with one other

Attempt to find the lowest energy structure

Sequences that have been selected during evolution to fold to globular structures, and requires only a very small number of all possible conformations needs be sampled during the search process

Alignment scoring schemesStochastic Search

Free energy (F) of the system = a function of the total number of contacts between residues (C) and the number of contacts that correspond to those of the most stable native structure(Q0)

Alignment scoring schemesContact Order

Correlation between the folding rates of small proteins and the“contact order” of their structures

Contact order = the average separation in the sequence betweenresidues that are in contact with each other in the nativeStructure

This correlation appears to be largely independent of other details of the protein folds, such as their size and secondary structure content (i.e. the helices and sheets that are seen in almost all native protein structures)

Due to very different architectures of secondary structure

Alignment scoring schemesEnergy Landscape

Alignment scoring schemesFast Track

“fast track” in which the two domains fold simultaneously and produce an intermediate (alpha/beta) and finally converts into native state

Alignment scoring schemesSlow Track

Folding from this intermediate involves either a transition over a higher barrier, or partial unfolding to enable the remainder of the folding to take place along a fasttrack

“slow track” - chain becomes trapped in a long-lived intermediate state with persistent structure only in the alpha domain

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