Protein structure

From DrugPedia: A Wikipedia for Drug discovery

A number of residues are necessary to perform a particular biochemical function, and around 40-50 residues appears to be the lower limit for a functional domain size. Protein sizes range from this lower limit to several thousand residues in multi-functional or structural proteins. However, the current estimate for the average protein length is around 300 residues.Very large aggregates can be formed from protein subunits, for example many thousand actin molecules assemble into a collagen filament.

A number of residues are necessary to perform a particular biochemical function, and around 40-50 residues appears to be the lower limit for a functional domain size. Protein sizes range from this lower limit to several thousand residues in multi-functional or structural proteins. However, the current estimate for the average protein length is around 300 residues.Template:Fact Very large aggregates can be formed from protein subunits, for example many thousand actin molecules assemble into a collagen filament.

Levels of protein structure

• Primary structure - the amino acid sequence of the peptide chains.
• Secondary structure - highly regular sub-structures (alpha helix and strands of beta sheet) which are locally defined, meaning that there can be many different secondary motifs present in one single protein molecule.
• Tertiary structure - three-dimensional structure of a single protein molecule; a spatial arrangement of the secondary structures. It also describes the completely folded and compacted polypeptide chain.
• Quaternary structure - complex of several protein molecules or polypeptide chains, usually called protein subunits in this context, which function as part of the larger assembly or protein complex.

In addition to these levels of structure, a protein may shift between several similar structures in performing its biological function. In the context of these functional rearrangements, these tertiary or quaternary structures are usually referred to as chemical conformation, and transitions between them are called conformational changes.

The primary structure is held together by covalent or peptide bonds, which are made during the process of protein biosynthesis or translation. These peptide bonds provide rigidity to the protein. The two ends of the amino acid chain are referred to as the C-terminal end or carboxyl terminus (C-terminus) and the N-terminal end or amino terminus (N-terminus) based on the nature of the free group on each extremity.

The various types of secondary structure are defined by their patterns of hydrogen bonds between the main-chain peptide groups. However, these hydrogen bonds are generally not stable by themselves, since the water-amide hydrogen bond is generally more favorable than the amide-amide hydrogen bond. Thus, secondary structure is stable only when the local concentration of water is sufficiently low, e.g., in the molten globule or fully folded states.

Similarly, the formation of molten globules and tertiary structure is driven mainly by structurally non-specific interactions, such as the rough propensities of the amino acids and hydrophobic interactions. However, the tertiary structure is fixed only when the parts of a protein domain are locked into place by structurally specific interactions, such as ionic interactions (salt bridges), hydrogen bonds and the tight packing of side chains. The tertiary structure of extracellular proteins can also be stabilized by disulfide bonds, which reduce the entropy of the unfolded state; disulfide bonds are extremely rare in cytosolic proteins, since the cytosol is generally a reducing environment.

Structure of the amino acids

An α-amino acid consists of a part that is present in all the amino acid types, and a side chain that is unique to each type of residue. The C_α atom is bound to 4 different molecules (the H is omitted in the diagram); an amino group, a carboxyl group, a hydrogen and a side chain, specific for this type of amino acid. An exception from this rule is proline, where the hydrogen atom is replaced by a bond to the side chain. Because the carbon atom is bound to four different groups it is chiral, however only one of the isomers occur in biological proteins. Glycine however, is not chiral since its side chain is a hydrogen atom. A simple mnemonic for correct L-form is "CORN": when the C_α atom is viewed with the H in front, the residues read "CO-R-N" in a clockwise direction.

The side chain determines the chemical properties of the α-amino acid and may be any one of the 20 different side chains:

Table I:

Name	3-letter Code	Single Code	Relative abundance % E.C.	Mol.Wt.	pK value	VdW volume	Charged, Polar, Hydrophobic, Neutral
Alanine	ALA	A	13.0	71		67	H
Arginine	ARG	R	5.3	157	12.5	148	C+
Asparagine	ASN	N	9.9	114		96	P
Aspartate	ASP	D	9.9	114	3.9	91	C-
Cysteine	CYS	C	1.8	103		86	P
Glutamate	GLU	E	10.8	128	4.3	109	C-
Glutamine	GLN	Q	10.8	128		114	P
Glycine	GLY	G	7.8	57		48	N
Histidine	HIS	H	0.7	137	6.0	118	P,C+
Isoleucine	ILE	I	4.4	113		124	H
Leucine	LEU	L	7.8	113		124	H
Lysine	LYS	K	7.0	129	10.5	135	C+
Methionine	MET	M	3.8	131		124	H
Phenylalanine	PHE	F	3.3	147		135	H
Proline	PRO	P	4.6	97		90	H
Serine	SER	S	6.0	87		73	P
Threonine	THR	T	4.6	101		93	P
Tryptophan	TRP	W	1.0	186		163	P
Tyrosine	TYR	Y	2.2	163	10.1	141	P
Valine	VAL	V	6.0	99		105	H

The 20 naturally occurring amino acids can be divided into several groups based on their chemical proporties. Important factors are charge, hydrophobicity/hydrophilicity, size and functional groups. The nature of the interaction of the different side chains with the aqueous environment plays a major role in molding protein structure. Hydrophobic side chains tends to be buried in the middle of the protein, whereas hydrophilic side chains are exposed to the solvent. Examples of hydrophobic residues are: Leucine, isoleucine, phenylalanine, and valine, and to a lesser extent tyrosine, alanine and tryptophan. The charge of the side chains plays an important role in protein structures, since ion bonding can stabilize proteins structures, and an unpaired charge in the middle of a protein can disrupt structures. Charged residues are strongly hydrophilic, and are usually found on the out side of proteins. Positively charged side chains are found in lysine and arginine, and in some cases in histidine. Negative charges are found in glutamate and aspartate. The rest of the amino acids have smaller generally hydrophilic side chains with various functional groups. Serine and threonine have hydroxylgroups, and aspargine and glutamine have amide groups. Some amino acids have special properties such as cysteine, that can form covalent disulfide bonds to other cysteines, proline that is cyclical, and glycine that is small, and more flexible than the other amino acids.

The peptide bond

Two amino acids can be combined in a condensation reaction. By repeating this reaction, long chains of residues (amino acids in a peptide bond) can be generated. This reaction is catalysed by the ribosome in a process known as translation. The peptide bond is in fact planar due to the delocalization of the electrons from the double bond. The rigid peptide dihedral angle, ω (the bond between C₁ and N) is always close to 180 degrees. The dihedral angles φ (the bond between N and Cα) and psi ψ (the bond between Cα and C₁) can have a certain range of possible values. These angles are the degrees of freedom of a protein, they control the protein's three dimensional structure. They are restrained by geometry to allowed ranges typical for particular secondary structure elements, and represented in a Ramachandran plot. A few important bond lengths are given in the table below.