Virtually every biochemical course of action in the living cell is catalysed, consistent and regulated by protein. While fundamentally dependent on the linear amino acid ordern, it is the precise folding of the polypeptide chain into a discrete three-dimensional structure (or conformation) that ultimately confers its biological function. Deviation from this ‘native state’ – i.e. by misfolding, damage, mutation or denaturation – can rule to abnormal, depleted or already absent proteins, all of which can be devastating to the cell.
Since protein folding is thought to occur spontaneously following mRNA translation, the question of how a protein achieves such structural accuracyn from billions of possibilities is not however fully understood. What is known, however, is that prions caused by protein manifolding are now being indicated in neurodegenerative diseases and cancer, consequently identifying and understanding the inner mechanisms of the folding course of action is a meaningful area of biomedical research. Given that the integrity of protein structure is so vital to effective cell function, this essay will analyze the various molecular forces which are known to contribute to its stability.
A protein folds into a three-dimensional structure according to the chemical similarities of its component amino acids. consequently, prior to the folding course of action the linear amino acid ordern must first be consolidated to serve as the basis for its spatial organization. This is achieved by peptide bonding which generates a resonance force to give stabilizing double-bond characteristics which are shorter, more stiff and have a planar arrangement preventing free rotation. This bond can resist de-naturation by normal methods (such as heat and urea) and can only be broken by hydrolysis with a strong acid or base at very high temperatures in the absence of enzyme activity. This establishes a strong covalent backbone which is also polar, allowing for hydrogen bonding.
Such hydrogen bonding between the established backbone NH-CO groups constitute a proteins secondary structure. Hydrogen atoms of the amine groups are attracted to the more electronegative carboxyl groups, resulting in electrons being shared. While a hydrogen bond in itself is non-covalent, the multiple repeated character of such bonding offers much stability. Many proteins characterize repeated patterns of hydrogen bonding to form α helices and β-pleated sheets, the latter being composed of short β strands (usually no more than 8 residues) laid out similar or anti-similar to each other with hydrogen bonds perpendicular to the polypeptide backbone. These structures can interact to form motifs often referred to as super-secondary structure and are shared in structural proteins like collagen and keratin. Branched amino acids (e.g. val or ile) can interfere with these arrangements if in large numbers, causing coils, loops and turns in the secondary structure – as too does proline because it has a secondary instead of a dominant amine group. However, instead of disrupt stability, these features allow close packing and closeness of variable side chains which can take part in further bonding.
Bonding between side-chainsgives rise to tertiary structure and this is what ultimately divides the protein into functional domains. Side chain interactions depend on their chemical similarities. One example of tertiary bonding is the formation of ionic bonds (or salt bridges) between charged amino acid side chains. for example, the negatively charged oxygen on an aspartic acid residue can bond to the positively charged nitrogen atom in lysine as an electrostatic force of allurement. Two cysteine residues can cross-link to form covalent disulphide bonds, which are important in stabilising smaller or extracellular proteins such as albumin. Serine and other polar uncharged amino acids contain hydroxyl groups that can hydrogen bond with water or hydrophilic residues such as glutamate acid, both of which are usually found on the surface of water soluble proteins. Phenylalanine and tyrosine, both aromatic and hydrophobic, can also form hydrogen bonds with other residues and the peptide backbone, in addition as forming special hydrophobic interactions called pie stacks. The complexity of these tertiary interactions transforms the protein into a functional unit.
Despite the fact that most functional residues are usually found on the protein surface, the major driving force for protein stability is thought to be the formation of a hydrophobic chief. Hydrophobic amino acids such as alanine and methionine will tend to cluster together in order to exclude water. This occurs because the hydrophobic amino acids have no, or small, electrical charges which would disrupt the normal hydrogen bonding between water molecules. By excluding these molecules, most of which have hydrocarbon side-chains, the protein structure is more thermodynamically stable and is entropy pushed at room temperature. Recent experiments using mutagenesis show that substituting amino acids on the surface does little to affect protein stability but substitutions at the protein chief can be severely destabilizing.