Protein Structure II: Digging Deeper

In the previous post, we discussed the different levels of protein structure.  Here, we will consider more specific details of what makes up protein structure.

Previously, we talked about how secondary structure consists of alpha helices and beta sheets, but there are even more nuanced forms of secondary structure.  For example,  different types of alpha helices exist:  the 3.613 and 310 helices are different types that consist of 3.6 and 3 amino acids per turn of the helix, they also have different radii and lengths.

An interesting little tidbit about alpha helices is that there are certain amino acids that are more likely to be found in helices.  These include alanine, glutamine, leucine, and methionine.  In contrast, there are some amino acids that do not really fit into a helix: proline, glycine, tyrosine, and serine.  These amino acids have structural characteristics (such as proline's "kink") that tend to break helix structure.

Additionally, beta sheets have different properties depending on their orientations.  For example, with a parallel beta sheet, the chains of the protein are oriented in the same direction.  In contrast, anti-parallel beta sheets have chains that run in opposite directions.  See the illustration for a more visual explanation of this trait.

In addition to beta sheets and alpha helices, a few more "secondary structures" exist.  I put this in quotation marks because these types of structures are perhaps not classical structures - in that they're not alpha helices or beta sheets.  The first is the loop, which is a stretch of amino acids that makes a loop - rather self-explanatory!  These loops are important for protein structure because they allow for the creation of relatively compact proteins.  In particular, loops can be found in anti-parallel beta sheets, connecting the two beta strands to make the sheet.  Sometimes these structures are called hairpins because they are tight stretches of amino acids that hold a protein structure together.

The last secondary structural element we'll consider is the crossover loop, which is similar to the hairpin loop, but it connects portions of a protein at a longer distances.  These crossovers can be found especially in anti-parallel beta sheets, connecting the two strands such that they can be anti-parallel.

As mentioned, secondary structure consists of small tracts of protein structure, primarily formed of alpha helices and beta sheets.  These secondary structural elements can be organized into specific combinations called motifs.  Motifs are commonly-found structural organizations in proteins, such as zinc finger or coiled coil motifs.  In the case of a zinc finger motif, there are two beta strands and an alpha helix, making up a fold that looks something like a finger.  Within this motif is a zinc ion, hence its name.  Several proteins contain this motif, which is primarily involved in DNA- and RNA-binding.

Another level of structure is the domain, which is considered a module of a protein.  In general, domains have functions that can be separated from the protein as a whole.  Domains are typically large pieces of proteins (think of them as a swing set on a playground - the playground is for kids to play, and the swing set has its own specific function, to swing!).  An interesting aspect of domains is that they can be found in multiple proteins with similar functions.  For example, some proteins have kinase domains to help with phosphorylation; some have RNA-binding domains; and so on.  By detecting domains within a protein, we can infer its function, and this ability has been incredibly useful in predicting the function of new proteins.

Amino Acids: The Building Blocks of Proteins

While I've written many posts describing signaling pathways and cellular phenomena of significant complexity, I'd like to use this post to take a step back and look at some fundamental building blocks, first turning to amino acids, the monomers that, when polymerized, make up polypeptides and proteins. At the most basic level, amino acids are really a rather simple chemical compound, consisting of a amino group, a carboxy group, a hydrogen, and a side chain, all sticking off a central carbon atom.  These amino acids are polymerized via their amino and carboxy chemical groups to create long, linear linkages.

Brief aside: In my chemistry class in undergrad, my TA helped us remember the order of the chemical bonds following polymerization by saying N-H, C-H, C-O, N-H, C-H, C-O, ...


You may remember briefly from any stint in chemistry class that a carbon atom that is covalently bound to four different chemical entities (in this case, a side chain, a hydrogen atom, a carboxyl group, and an amino group) can take two different conformations, depending on how these bonds are spatially oriented.  In the case of amino acids, the vast majority of amino acids found in our bodies and used to generate proteins are L stereoisomers.  This is a result of the amino acid synthesis machinery structure exclusively generating L amino acids.  There are exceptions, but we won't get into that.

As I mentioned, amino acids have a side chain: the part of the amino acid that endows it with its identity.  These side chains can be broken into a few groups that we will explore now:

The first set of side chains is the nonpolar, hydrophobic side chains.  The amino acids in this group include alanine, valine, leucine, isoleucine, glycine, methionine, and proline (structures shown to the right).  What you'll immediately notice is that these amino acid side chains are composed mostly of hydrogens and carbons.  Thus, these side chains do not contain polar covalent bonds and do not interact as readily with water (thus the term hydrophobic - they're "afraid" of water.  Some amino acids of note in this group are proline, which contains a ring structure that creates a "kink" in the amino acid, and methionine, which contains a sulfur atom.

The next set is composed of the aromatic side chains, which includes phenylalanine, tyrosine, and tryptophan.  These amino acids all contain an aromatic ring, which makes them relatively nonpolar; thus, they do not interact favorably with water.  These amino acids are involved in mediating protein protein interactions and are frequently found at the active sites of enzymes.

Next up: polar, uncharged side chains: asparagine, cysteine, glutamine, serine, and threonine.  These amino acids contain hydroxyl, sulfhydryl, or amide groups that mediate interactions with water, but they carry no net charge.  An amino acid of note in this family is cysteine, which can react with itself to form cystine, which is important in mediating the formation of disulfide bonds in protein structures.

We'll consider basic side chains next.  These amino acids consist of arginine, histidine, and lysine, which all carry a net positive charge in solution.  Of note, histidine is commonly found at the active site of enzymes to serve as a protein donor or acceptor.

Finally, we find acidic side chains: aspartate and glutamate.  In solution, these amino acids carry a negative charge and are considered acidic.

In the diagram at right, I've drawn up each of the amino acids along with their three-letter and one-letter codes.  These codes are frequently used to abbreviate long lists of amino acids.

Another brief aside:  Did you know that a single woman designated the amino acid abbreviations?  She chose letters that made sense for most amino acids (as you can see above).  For tryptophan, for example, she chose W because she envisioned saying tryptophan as twyptophan.  Kind of cool, huh?


As a summary, here are the amino acid abbreviations:

• A, ala, alanine
• C, cys, cysteine
• D, asp, aspartate
• E, glu, glutamate
• F, phe, phenylalanine
• G, gly, glycine
• H, his, histidine
• I, ile, isoleucine
• K, lys, lysine
• L, leu, leucine
• M, met, methionine
• N, asn, asparagine
• P, pro, proline
• Q, gln, glutamine
• R, arg, arginine (think aRRRRginine)
• S, ser, serine
• T, thr, threonine
• V, val, valine
• W, trp, tryptophan (tWWWyptophan)
• Y, tyr, tyrosine

So there you have it: 20 amino acids.  In addition to these amino acids, our bodies contain several more, including selenocysteine (identical to cysteine but containing selenium rather than sulfur) and ornithine (remember this from glycolysis?).  Amino acids can also undergo modifications: for instance, lysine residues can be acetylated.  More amino acids and their variants are always being discovered as well.

Now that we have the building blocks of proteins established, the next blog post will focus on how these amino acids can be combined (polymerized) into long structures that make up polypeptides and proteins.