Structure

Structure and Function

Proteins, which are long chains of amino acids, are indispensable for living things. They perform both function roles (such as enzymes and hormones) and structural roles (such as collagen and hair).

In biological proteins, structure and function go hand in hand; the structure determines the function, and the function is completely dependent upon the structure. By structure, we mean the three-dimensional shape (“conformation”) assumed by the chain of amino acids after the cell has synthesized it. Usually this is a globule (like a small wad of yarn); many structural proteins assume a more fibrous conformation. These conformations can look kind of random to us, but a protein's shape must be exactly right for it to perform its function.

Predicting Structure from Sequence

The conformation assumed by each protein is completely determined by the laws of physics and chemistry. Each amino acid in the chain has either a water-loving or water-hating preference, and inside the cell’s watery environment, the chain tries to fold up in such a way as to “please” all these preferences. See Compactness for more on this.

Since any given chain of amino acids has only one stable low energy conformation (its native conformation), and this native conformation is determined by known laws, you might think it would be simple to predict a protein’s structure just from its amino acid sequence. Not so. The chain can fold up in so many ways that there are just too many possibilities for even a computer to sort through. Protein structure prediction has long been a holy grail for scientists.

The goal of Foldit, of course, is to see if humans can determine correct protein structures using some excellent computer tools. Knowing a protein’s correct structure gives scientists a big advantage when trying to design drugs and diagnostics that relate to that protein.

How Scientists Make Sense of the Protein Snarl

So, what do we mean when we say structure? Aren’t proteins just balls of snarled yarn? Yes, but very organized snarls of yarn. Scientists break it down this way.

Primary structure is the sequence of amino acids that are joined in a chain by peptide bonds. Shape is not relevant in the primary structure, only sequence.

When two amino acids are joined by a peptide bond, they form a so-called dipeptide, and three amino acids in a chain form a tripeptide, whereas the full protein is referred to as a polypeptide. The polypeptide has directionality, with the first amino acid forming an amino terminus (N-terminus), where the amino group (-NH2) is free and not attached to another amino acid. The last amino acid on the other hand has a free carboxyl group (-COOH) and is referred to as carboxy terminus (C-terminus). This directionality has no importance in folding, however.

The human proteins are made of 20 different amino acids (residues) and most normal polypeptides consist of 50 to 2000 residues.

Secondary structure refers to the three-dimensional, local shapes that serve as building blocks for all proteins. These are helices (also called alpha-helices, which show as spirals) and sheets (also known as beta-sheets, which show as ribbons). They come in different sizes, but the essential shapes are the same. Every protein will have at least one of these structures, and usually several. Secondary structures serve principally to stabilize the core of the protein. The secondary structures are stabilized by hydrogen bonds.

Although they are not “regular” secondary structures, we can also talk about loop regions — the sections that connect up the helices and sheets. These loops can be of many lengths and shapes. Although they don’t share one common shape, they are frequently involved with the function of the protein. Getting their conformation correct is just as important as it is for helices and sheets.

Tertiary Structure refers to the 3D conformation of the fully folded protein in its entirety. Usually this means the same thing as the protein’s native structure. The tertiary structure is stabilized by hydrogen bonds, salt bridges and disulfide bonds, and also by formation of a hydrophobic core.

Quaternary Structure. Some proteins are made up of multiple, separate proteins (called "subunits") that join together in order to be functional. Hemoglobin, for example, is made up of four subunits arranged in a certain way. Quaternary structure refers to the particular arrangement of protein subunits.

Since most Foldit puzzles consist of proteins that contain only a single subunit, quaternary structures are generally not relevant in most cases. However, quaternary structures can be found in symmetry puzzles, which feature proteins that contain multiple identical subunits.

What do the structures do?

'Secondary structures are patterns that pop up over and over again in naturally-occurring protein structures. They form for two reasons:

• First, every amino acid in a stretch of secondary structure is in a good conformation for avoiding clashes, both with itself, and with other amino acids in the structure. (There exist some conformations, for example, in which an amino acid's backbone oxygen clashes with the first carbon atom in its side chain. This clash does not happen in either alpha-helices or in beta-strands, though.)

• Second, the backbone hydrogen bond donors and acceptors can by fully satisfied by bonding to other amino acids within the same piece of secondary structure (in the case of helices), or in adjacent pieces of the same type of secondary structure (in the case of strands).

Both of these things make helices and sheets very energetically favourable -- i.e. very stable, which is why they form spontaneously. It is difficult to create a loop in which all the backbone hydrogen bonds are fully internally satisfied, which is one reason why you tend not to see very many large proteins that have no secondary structure at all.'

—V Mulligan 2014; More comments on secondary structures: http://fold.it/portal/node/998291

Secondary Structure and Foldit

Although our ultimate goal in Foldit is to figure the tertiary / native structure for each protein puzzle, we spend a lot of time messing with secondary structures, moving, rearranging, and perfecting them. So it makes sense to learn a little about ideal secondary structures (helices, sheets, and loops) and what makes them happy. You can read more information on Foldit's treatment of Secondary Structure.

See also Protein Folding Theory and Online Resources