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Conformational Stability of Proteins

Conformational Stability of Proteins

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Published by: Md.shakhaowat Hossain on Jan 13, 2011
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Conformation Stability of Proteins
Protein stability and folding
Upon biosynthesis, a polypeptide folds into its native conformation which is structurally stable andfunctionally active.
The conformation adopted ultimately depends upon the amino acid sequence of polypeptides, whichexplains why different polypeptide types have different characteristic conformations.The major stabilizing forces of a polypeptide’s overall conformation are:
Hydrophobic interactions
Electrostatic interactions
Covalent linkages
Hydrophobic interactions
Hydrophobic interactions are the single most important stabilizing influence of protein nativestructure.
The “hydrophobic effect” refers to the tendency of non-polar substances to minimize contact with a polar solvent such as water.
 Non-polar amino acid residues constitute a significant proportion of the primary sequence of virtually all polypeptides.
These polypeptides will fold in such a way as to maximize the number of such non-polar residue sidechains buried in the polypeptide’s interior away from the surrounding aqueous environment. Thissituation is most energetically favorable.
Electrostatic attraction
Stabilizing electrostatic interactions include:
Van der Waals forces − which are relatively weak 
Hydrogen bonds
Ionic interactionsAlthough nowhere near as strong as covalent linkages, the larger number of such interactions existingwithin a polypeptide renders them collectively quite strong.
Table: -
Approximate bond energies associated with various (non-covalent) electrostatic interactions, ascompared to a carbon-carbon single bond
Bond typeBond strength (kj/mol)
Van der Waals forces10Hydrogen bond20Ionic interactions86Carbon-carbon bond350
Covalent linkages
Disulfide bonds represent the major covalent bond type which can help stabilize polypeptides native 3-Dstructure.Intracellular proteinsAlthough generally harboring multiple cystein residues, these rarely form disulfide linkages, due to thereducing environment which prevails inside the cell.Extracellular proteinsIn contrast, these are usually exposed to a more oxidizing environment, conductive to disulfide bondformation.
In many cases the reduction (i.e. breaking) of disulfide linkages has little effect upon the polypeptide’s native conformation.
However, in other cases (particularly in disulfide rich proteins) disruption of this covalent linkagedoes render the protein less stable conformationally.
In these cases the disulfide linkages likely serve to ‘lock’ functional and/or structurally importantelements of domains- tertiary structure in place.
Proteins are static, rigid structures; but this is not the case.
A protein’s constituent atoms are constantly in motion and groups ranging from individual aminoacid side chains to entire domains can be displaced via random motion by anything up toapproximately 0.2 nm.
A protein’s conformation therefore displays a limited degree of flexibility and such movement istermed “breathing”
Breathing can sometimes be functionally significant by, for example, allowing small molecules todiffuse in/out of the protein’s interior.
In addition to breathing, some proteins may undergo more marked (usually reversible)conformational changes. Such changes are usually functionally significant. Mot often they areinduced by biospecific ligand interactions (e.g. binding of a substrate to an enzyme or antigen binding to an antibody)
Factors influencing intrinsic stability
The factors influencing the intrinsic stability of native polypeptide conformation have largely beenelucidated via the study of proteins which function under relatively mild environmental conditions.
3-D structure of a number of homologous proteins derived from various psycrophiles, mesophiles,thermophiles and hyperthermophiles have now been determined.2
This facilitates the identification of changes in structural features that helps render the protein stableunder its particular native physiological conditions.
Thermodynamics analysis reveals that the of marginal stability between the native versusdenatured state extends to proteins isolated from such extreme environments.
It might be expected that proteins isolated from thermophiles and hyperthermophiles would exhibitan increased level of intramolecular stabilizing interactions, in order to compensate for thedestabilizing influence of elevated temperature.
Conversely, it could be predicted that, in order to remain at appropriate degree of conformationalflexibility, proteins from psychrophiles would display decreased levels of such stabilizinginteractions.
Thermal stability
Increased thermal stability is generally related to one or more of the following structural adaptations:
An increase in the number of intramolecular polypeptide hydrogen bonds.
An increase in the number of salt bridges.
Increased polypeptide compactness (improved packing of hydrophobic regions)
Extended helical regions.
 Stability of proteins derived from psychrophiles
Enhanced stability/functional flexibility of proteins derived from psychrophiles appear to be achieved byone or more of the following adaptations:
Fewer salt links
Reduced aromatic interactions within the hydrophobic core (reduction in hydrophobicity)
Increased hydrogen bonding between the protein surfaces of the surrounding solvent.
Occurrence of extended surface loops.
Conformational stability of proteins
The stability of a protein, i.e. its usefulness as a biologically active molecule, depends on the particular environment and the exposure to conditions that can promote chemical deterioration or conformationalchanges.
1.in vivo stability
Under in vivo condition, protein stability (turnover) is governed by the action of proteolyticenzymes.3

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