All proteins bind to other molecules. Any molecule that is bound by a protein is referred to as a ligand, from the Latin 'ligare' meaning 'to bind'. The ability of a protein to bind to or interact with a ligand depends on the formation of weak, non-covalent bonds between them. This process relies on the sequence of amino acids in each protein and the way in which their side chains (or R groups) interact with each other. Different side chains can form different bonds. Because of this, protein interactions can be very specific.
There are several ways of classifying the 20 amino acids, but for the purpose of this article, I have classified them by their chemical properties, as this will affect the types of bonds they can take part in. The aliphatic (Gly, Ala, Val, Leu, Ile, and Pro) and aromatic (Phe, Tyr, Trp) amino acids are essentially non-polar and therefore interact mainly via hydrophobic interactions and Van der Waals forces. Hydrophobic interactions occur because of the change in entropy when non-polar groups are exposed to water which means they are more stable if they are close to each other excluding water. Van der Waals forces occur as a result of an atom's fluctuating electrical charge. At any one moment in time, an atom has an electrical dipole across it due to the random movement of electrons. This induces a temporary charge in a neighbouring atom by attracting or repelling the electrons associated with it, resulting in a temporary attractive force between the two atoms.
Acidic (Asp, Glu) and basic (Arg, Lys, His) amino acids take part in charge-charge interactions or ionic bonds because they are charged. These tend to be stronger than the charge-charge interactions between amino acids that contain alcohols (Ser, Thr, Tyr) or amides (Asn, Gln) R groups which are polar due to the 'O' and 'N' atoms drawing electrons toward themselves. These also tend to be the amino acids that are better at Hydrogen bonding because they are polarised. Hydrogen bonds occur between the Hydrogen of an N-H or O-H group on one amino acid, and the lone pair on an Oxygen or Nitrogen atom of an adjacent amino acid.
Cysteine residues can form disulphide bridges either within a peptide, or between two polypeptide chains to join them together. These disulphide bonds are covalent bonds and unlike the other types of bond discussed do not form spontaneously in protein-ligand interactions, requiring a catalyst to join and break them.
Proteins bind to other proteins for many reasons including inhibition, signalling, catalysis and producing macrostructures e.g. collagen filaments. For example, antibodies are Y shaped proteins of the immune system that recognise and bind to other proteins, called antigens. Antibodies display remarkable specificity. A person will encounter billions of different antigens in their lifetime, but a specific antibody is produced for each. The structure of all antibodies is essentially the same, with only the antigen-binding site varying between them. The antigen-binding site consists of several loops of polypeptide chain that protrude from each arm of the antibody and makes one antibody target a specific antigen. The enormous diversity of antigen-binding sites is created simply by changing the amino acid sequence of these loops. The presence of these different amino acids means that, as we have seen, different bonds can be formed between the antibody and the antigen.
The only function of an antibody is to bind to another protein, an antigen. However, for other proteins, binding to the ligand is merely the first step. Enzymes are complex proteins produced by living cells that catalyse specific biochemical reactions without undergoing change themselves. This relies on the enzyme having an active site that is specific for a particular substrate. The correct binding of reactant to active site provides both the specificity of the reaction and the catalytic power of the enzyme. The binding forces responsible for enzyme-substrate recognition are mostly the same non-polar interactions discussed above.
The image here shows the binding pockets of two very similar serine proteases; trypsin and chemotrypsin. Substrate specificity is determined by the binding interactions discussed in this article. Chemotrypsin cuts peptide chains after large hydrophobic amino acids but the negatively charged residue in the binding pocket of trypsin makes it specifically cleave after positively charged residues. Replacing this one residue in trypsin with a serine is enough to partially convert it to chemotrypsin, highlighting how important these interactions are.
Proteins can also bind to and interact with DNA either specifically orhttp://www.fastbleep.com/me/notes/article/editcontentbox/13015?msg=Changes+Saved non-specifically. Histones are structural proteins that bind DNA in a non-specific way. Histones are responsible for the primary level of chromatin packing in eukaryotic cells. The histones form a complex called a nucleosome, and the DNA is wound around it, rather like beads on a string. These non-specific interactions rely on the formation of ionic bonds between the basic amino acid residues in the histones and the acidic sugar phosphate backbone of the DNA. It does not depend on the base pairs present in the DNA sequence. Chemical alterations to the basic residues in the histones, such as methylation and phosphorylation, can alter the strength of these interactions, making the DNA more or less tightly packed. This can affect transcription.
Transcription factors are proteins that regulate transcription of genes by binding to DNA in a specific way. Each transcription factor will only bind to a particular DNA sequence. These DNA sequences are usually in or close to the gene promoter. Once assembled at the promoter, the transcription factors position the RNA Polymerase and pull the double helix apart to expose the template strand of the required gene to allow transcription to begin. These specific interactions depend on the different bases present in the DNA strand, because this will affect which transcription factors can bind.
Many of the drugs that we take bind selectively to target proteins in the body. The main types of target proteins are receptors, enzymes, ion channels and DNA. Pharmacologists prefer a drug that has a higher affinity for its target, that is, it binds more tightly to it, because it means that lower doses can be used.
Receptors are proteins or protein complexes located either inside the cell or on the cell surface membrane. Often they are transmembrane proteins that relay signals by binding a ligand on one side of the membrane, altering their conformation on the other side to transmit a signal for example activating a kinase internal domain. Receptors recognise many ligands, including neurotransmitters, hormones and drugs. The interactions between the receptor and the ligand again depend on the amino acids in the receptor and the bonds they can form with atoms in the ligand. Once bound, a ligand can induce a response in the target cell.
Drugs that target enzymes usually act by reversible enzyme inhibition. Inhibitors bind to an enzyme and prevent either the formation of the enzyme-substrate complex or catalysis to enzyme and product. Competitive inhibitors bind to the active site of the enzyme and therefore usually resemble the substrate in shape and chemical composition. Non-competitive inhibitors bind to a site other than the active site. The binding of this type of inhibitor affects the shape of the enzyme active site so that the substrate can still bind, but it will not be converted into product. One unusual example of a drug's action on an enzyme is Aspirin. Aspirin (acetylsalicilic acid) is a common anti-inflammatory medicine used to relieve minor aches, pains and fever. What makes Aspirin unusual is that it binds irreversibly to the enzyme cyclooxygenase (COX), causing complete inactivation. This occurs via a covalent bond between the acetyl group in the Aspirin and a serine residue in the active site of the COX enzyme.
The order of amino acids in a protein is responsible for its shape and ability to function, but for some proteins, they need to employ a little help from small non-protein molecules. Haemoglobin is a protein found in the red blood cells of all vertebrates. It helps transport oxygen around the body, but would not be able to carry out this vital function if it were not for the role of iron atoms. A molecule of haemoglobin carries four non-covalently bonded heme groups, which are ring-shaped molecules with a single central iron atom. This iron atom binds reversibly to dissolved oxygen and enables the haemoglobin protein to transfer it from the lungs to the tissues.
Enzymes, too, make use of non-protein molecules. Carboxypeptidase is an enzyme that cleaves polypeptide chains. It carries a zinc ion in its active site which forms a temporary bond with one of the substrate atoms, thereby allowing the cleavage of the peptide bond to occur.
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