The extraordinary chemical adaptability of proteins frequently requires interactions between the chemical groups that are found on their surface. These interactions boost the chemical reactivity of one or more of the amino acid side chains. These encounters can be broken down into two distinct categories.

To begin, the contact between neighboring segments of the polypeptide chain may block water molecules from accessing the ligand-binding sites on the protein. Because water molecules readily form hydrogen bonds, which can compete with ligands for sites on the protein surface, it is important to keep water molecules out of the way when a ligand is trying to form hydrogen bonds (and electrostatic interactions) with a protein. This will allow the hydrogen bonds to become much stronger. It may be challenging to conceive of a method that may prohibit a water molecule from accessing the surface of a protein without also having an effect on the ligand itself. However, individual water molecules can make a substantial number of hydrogen bonds with other water molecules, leading to the formation of a dense network of hydrogen bonds. A protein is able to effectively keep a ligand-binding site dry, which in turn increases the site's reactivity. This is made possible by the fact that it is energetically unfavorable for individual water molecules to break away from this network, which is what they must do to reach into a crevice on the surface of a protein.

Clustering can also alter the reactivity of the polar amino acid side chains of neighboring amino acids, which is the second point. For instance, the affinity of the site for an ion with a positive charge can be considerably increased if the folding of the protein brings together multiple negatively charged side chains in contrast to the attraction that would normally exist between them. Because of this, the surface of each protein molecule has a unique chemical reaction that is influenced by both the amino acid side chains that are exposed and their precise orientation in relation to one another. As a result of this, the surface of each protein molecule can be distinguished from one another. As a consequence of this, the chemistry of two slightly different conformations of the same protein molecule may change significantly from one another.

Genome sequences allow us to group a huge number of protein domains into families that unambiguously illustrate how they originated from a common ancestor, as we have previously demonstrated. This is made possible by the fact that these families can be linked back to the original genome. The three-dimensional structures of members of the same domain family are strikingly similar to one another. For example, even if there is just a 25% similarity in the amino acid sequence between two domains, the backbone atoms in each domain can nonetheless adhere to the same protein structure within 0.2 nanometers (2) of each other.

We can make use of a method known as evolutionary tracing in order to identify the regions of a protein domain that are most crucial to the domain's functionality and target those regions. The regions of an organism that are responsible for binding to other molecules have a greater chance of avoiding change as the organism evolves. Therefore, in this method, the amino acids that are identical to or nearly identical in every member of a protein family are projected onto a model of the three-dimensional structure of that protein family member. Through the SH2 domain, a connection can be made between two proteins. It does this by linking the protein that contains it to another protein that, in a particular context involving the sequence of amino acids, also has a phosphorylated tyrosine side chain. The prolonged evolutionary process that resulted in the enormous SH2 family of peptide recognition domains was particularly slow to evolve the amino acids in the binding site for the phosphorylated polypeptide. This was due to the fact that the SH2 family was already quite large when the process began. The process of survival is purposeful, while the process of mutation is not. As a consequence of this, natural selection, which involves the occurrence of random mutations followed by non-random survival, is responsible for the conservation of sequences. This occurs because natural selection eliminates animals whose SH2 domains change in a manner that renders the SH2 binding site inactive and, as a consequence, the SH2 function ineffective.

The sequencing of the genome has led to the discovery of a great number of proteins with as-yet-unknown functions. After the three-dimensional structure of one member of a protein family has been determined, evolutionary tracing enables researchers to identify binding sites for members of a protein family, which provides them with a helpful head start in understanding the function of proteins.

Proteins can attach to one another through a variety of different mechanisms. Regular interactions take place between a region on the surface of one protein and an extended polypeptide chain loop (sometimes referred to as a "string") on the surface of another protein. As an example, a surface-string connection like this one makes it possible for a protein kinase to recognize the proteins that it will phosphorylate, and it also makes it possible for the SH2 domain to recognize a phosphorylated polypeptide loop on a second protein, as was discussed just now. A second variety of protein-protein interface is produced when two helices, one originating from each protein, hook up to form a coiled-coil structure. There are a lot of different protein families that regulate genes that contain this form of protein interface. However, the most common way that proteins interact is when the hard surfaces of one molecule perfectly match the hard surface of another molecule. Interactions of this kind can be highly robust due to the fact that multiple weak links might form between two surfaces that are strikingly similar to one another. This same line of thinking also explains why surface-surface interactions may be so specific, which enables a protein to select just one partner out of the tens of thousands of different proteins that are present in a cell.

In order for proteins to carry out the myriad of tasks assigned to them, it is necessary for particular ligands to bind to the proteins. One of the most notable characteristics of the antibody family is its capacity to bind strongly and with a high degree of specificity. Antibodies, often referred to as immunoglobulins, are produced by immune systems in reaction to foreign molecules, such as those that are located on the surface of an invasive microorganism. Each antibody develops a strong association with a particular target molecule, which either renders the target molecule inert or identifies it as a candidate for elimination. An antibody has a high degree of specificity when it comes to recognizing its target, which is also referred to as an antigen. Because there are potentially billions of distinct antigens that humans could come into contact with, we need to have the ability to produce billions of different antibodies.

A little region on the surface of the antigen molecule is complementary to two identical binding sites on the Y-shaped molecules that constitute antibodies. According to a comprehensive analysis of these sites, antibody antigen-binding sites are made up of numerous polypeptide chain loops that stretch from the ends of a pair of closely spaced protein domains. This information was gleaned from analyzing these sites in great detail. A wide range of antigen-binding sites can be provided by a variety of antibodies by only adjusting the length and amino acid sequence of certain loops within the protein, without making any changes to the core protein structure.

These kinds of loops are very effective at entrapping other molecules. They make it possible for a ligand to be encircled by a large number of chemical groups, which allows a protein to connect to it by means of a large number of weak bonds. As a consequence of this, the ligand-binding sites of proteins typically take the shape of loops.