Alpha Helix Disruption: Videos & Practice Problems

Alpha helices can be disrupted by several factors, including their environment, amino acid interactions, and specific residues. Hydrophobic regions favor alpha helix formation, while hydrophilic areas disrupt it by competing for hydrogen bonds. Bulky or charged residues can destabilize helices through steric hindrance or repulsion. Additionally, glycine's small size and proline's lack of a hydrogen atom on its amino group create structural challenges, with proline being particularly disruptive. Understanding these factors is crucial for grasping protein structure and function.

Alpha Helix Disruption

Gonna talk about alpha helix disruption. So, there are actually several factors that can disrupt alpha helices and prevent the formation of alpha helices. And we're gonna talk about 3 of them down below in our example, numbered 1, 2, and 3. And these correspond with the numbers that are down below in our example 123. And what you'll notice is that we've got a 4th factor here that's not listed above and that's because we kind of already talked about it in our previous videos. So, it's not gonna be really much new information to you guys. And so, we'll revisit it once we get here in our example below. So, number 1 says that alpha helices are typically found spanning, so they're found spanning the hydrophobic area within a membrane. So this isn't a full 100% requirement of alpha helices, but what we'll tend to see throughout our course is that, transmembrane proteins or proteins that span a membrane within the hydrophobic region. So, this region right here, this represents a lipid bilayer, and this is going to be the hydrophobic region. In this hydrophobic region, what we have is, the protein takes on an alpha helix conformation. But in the hydrophilic region, the water-loving region which is right up above, these regions here do not form alpha helices, and we'll see that's gonna be the case for a lot of different situations. And that's because hydrophilic environments compete for hydrogen bond formation and disrupt alpha helices.

So, the second one is that alpha helices are quite sensitive and they're sensitive to destabilizing interactions between neighboring amino acid residues. So, if you have a bunch of bulky residues, right next to each other, bulky residues meaning really big r groups such as tryptophan's r groups, if you had a bunch of tryptophans in a row, then there would be a lot of steric hindrance between those r groups, and that might destabilize the alpha helix structure. And the same goes with the charged groups. And so, in our example down below, we're showing that how the pH of the solution and charged r groups can actually destabilize the alpha helix structure through repulsions. And so we can see that through polyglutamate, which is shown here, all polyglutamate is a protein that contains only glutamate amino acid residues, and also polylysine which is below. And so on this graph over here, all it's showing is the pH on the x-axis, and then on the y-axis, we have specific rotation. But really, you don't need to know about specific rotation. It's just measuring the structure of the alpha helix. And notice that when polyglutamate is at low pH's, basically pH's below this range right here, that the polyglutamate is able to take on the alpha helix structure. However, as soon as you raise the pH above this pH right here, notice that the structure of polyglutamate changes from the alpha helix to a random conformation. And that's because once it reaches this pH right here, any pH above that, glutamate r groups are going to be charged, negatively charged. And when all of these glutamates are negatively charged, they're gonna repel each other. And when they repel each other, they're gonna take on a random conformation instead of taking on the alpha helix conformation. And that's really all this is trying to say. And so the same applies for polylysine which is down below. With the polylysine, which only has a bunch of lysines, that corresponds to the red and so notice that when the pH is above a certain region, so above this pH right here, it corresponds with an alpha helix structure. But once the pH goes below this pH right here on the x-axis, basically, what that's saying is that it's going to lose its structure and it takes on a random conformation which is down below. And that's again because at this pH below that pH, lysine is gonna be in its conjugate acid form, which is gonna have positive charges, and all of these positive charges right next to each other are gonna repel each other and that's gonna destabilize the alpha helix structure. So again, all number 2 is saying is that if you have too many charged groups right next to each other at a certain pH, that's going to disrupt the alpha helix structure.

So, the third and final new factor that we're gonna talk about is that all alpha helix residues must have the same configuration. They must have the same configuration. And so, down below, what you can see is that, remember, the configuration is referring to the chirality of the amino acid residues. And so if you know that all residues must have the same configuration, a configuration of just a single residue can actually disrupt the structure of the alpha helix. So remember that most life predominantly uses L amino acids, not D amino acids. So, if you were to have a D amino acid in your alpha helix structure, then that could disrupt the alpha helix structure. And so that's all number 3 is saying. And then of course, our 4th factor here, which we kinda already know about, is just taking into account the dipole of the amino of the alpha helix. So, remember that the amino terminus over here has a partial positive charge, and the carboxyl terminus, which is over here, has a partial negative charge. And so we already know that if we put negatively charged amino acids by the amino end, that's gonna create a stabilizing effect. But if we put positively charged, like charges, on the amino terminus of the alpha helix, that's gonna create a destabilizing effect. So we kinda already talked about this previously, and the opposite applies for the carboxyl end. If we put negatively charged amino acid residues by the carboxyl end of the alpha helix, that's gonna be destabilizing. That's gonna disrupt the structure because like charges repel one another. But if we put a positive charge over here, that's going to promote the structure and create a stabilizing effect. So, that's all number 4 is saying. So, this concludes our lessons on the disruption of alpha helices and we'll talk about our final, our 5th and final factor disrupting alpha helices in our next lesson video. But first, we're gonna get some practice with these four factors. So I'll see you guys in that practice video.

Why does poly-L-Glutamate adopt an α-helical structure at low pH but a random conformation above pH 5?

• A. Positively charged residues destabilize α-helices.
• B. At high pH, the (-) Glu repulsion destabilizes α-helices.
• C. Negatively charged residues destabilize α-helices.
• D. < pH 5, the (+) Glu repulsion destabilizes α-helices.

Answer: (B)

Alpha Helix Disruption

So the last factor that we're going to talk about for alpha helix disruption is the idea that glycine and proline residues disrupt alpha helices. We already know that alpha helix formation requires a very particular set of phi and psi bond angles, and they need these phi and psi bond angles to stabilize the required hydrogen bonds for alpha helix formation. We know that alpha helix bond angles appear in the lower left-hand quadrant of the Ramachandran plot. Below, you will see that our alpha helix appears in the lower left-hand quadrant. The major idea that I want you to understand from this video is that glycine and proline residues disrupt alpha helices. This is significant because they destabilize alpha helices for different reasons. Glycine's R group is merely a hydrogen, so it is simply too small, and its size does not allow steric hindrance to limit its bond angles enough to conform to the alpha helix bond angles.

Proline's residue majorly disrupts alpha helices because it lacks a hydrogen atom on its amino group necessary for forming hydrogen bonds, creating a kink in the alpha helix chain. Prolines are significantly more disruptive than glycines. Glycines disrupt alpha helices but not nearly as much as prolines. Prolines are like alpha helix murderers, and they are almost never found in alpha helices. In our example below, we will discuss how glycine and proline disrupt alpha helices just by looking at their plots. Over here on the far left, notice that this is the typical Ramachandran plot of most amino acids, and notice that the alpha helix falls into the lower left quadrant as mentioned earlier. This is the right-handed alpha helix. The left-handed alpha helix, remember, is super rare and falls into the upper right quadrant.

Regardless of which alpha helix we are discussing, if we examine glycine's Ramachandran plot here in the middle, remember it has permissible bond angles in all four quadrants. When you look at these regions right here where the alpha helices fall, you will see that it is really hard to restrict glycine to these particular red regions because glycine has several other permissible regions. This shows why it is hard for glycines to be found in alpha helix structures. Now, if we examine proline, proline's Ramachandran plot shows that for the left-handed alpha helices, proline does not have any permissible angles to allow for that conformation. For the right-handed alpha helices, there seems to be a slight overlap. There are not any dark regions that cover the alpha helix region, but there are some permissible regions. The major reason prolines are disruptive to alpha helices is that they lack a hydrogen atom necessary for hydrogen bonding due to its cyclic R group that attaches back to its amino group. Again, the biggest conclusion for you to take from this is that both glycine and proline are disruptive to alpha helices, but prolines are even more disruptive than glycines. We will apply these concepts in our practice problems, so I will see you there.

An α-helix would be destabilized most by:

• A. DNA missense mutation leading to a Gly residue placed in the α-helix sequence.
• B. Interactions between neighboring Asp & Arg residues.
• C. A hydrophobic environment competing for hydrogen bonds.
• D. DNA missense mutation leading to a Pro residue placed in the α-helix sequence.
• E. A net electric dipole spanning several peptide bonds throughout the α-helix.

Answer: (D)

At pH 6.8, which of the following peptides is least likely to form an α-helix?
Peptide # 1: RSEDNFGAPKSILWE                    Peptide # 2: DQKASVEMAVRNSGK

• A. Peptide # 1.
• B. Peptide # 2.
• C. Both peptides are equally likely to form an α-helix.
• D. Neither peptide is likely to form an α-helix.

Answer: (A)

Why does proline often 'break' an alpha helix?

• A. Its amino group has no free hydrogen to bond with a carbonyl because of the imino ring.
• B. It is impossible for it to adopt the psi and phi angles required to form an alpha helix.
• C. Its peptide bond often adopts the trans conformation, unlike other amino acids.
• D. Its peptide bond flips frequently between the cis and trans conformations.

Answer: (A)

Here’s what students ask on this topic:

What factors disrupt alpha helices in proteins?

Several factors can disrupt alpha helices in proteins. Hydrophilic environments compete for hydrogen bonds, preventing alpha helix formation. Bulky or charged amino acid residues can cause steric hindrance or repulsion, destabilizing the helix. Glycine, due to its small size, and proline, which lacks a hydrogen atom on its amino group, also disrupt alpha helices. Proline is particularly disruptive because it creates a kink in the helix structure.

How do hydrophilic environments disrupt alpha helices?

Hydrophilic environments disrupt alpha helices by competing for hydrogen bonds. In these environments, the protein backbone forms hydrogen bonds with water molecules instead of with itself, preventing the formation of the alpha helix structure. This competition for hydrogen bonds destabilizes the alpha helix, favoring random coil conformations instead.

Why do glycine and proline residues disrupt alpha helices?

Glycine disrupts alpha helices because its small size allows for too much flexibility, making it difficult to maintain the specific bond angles required for helix formation. Proline disrupts alpha helices because it lacks a hydrogen atom on its amino group, which is necessary for forming hydrogen bonds. Additionally, proline introduces a kink in the helix due to its cyclic structure, making it particularly disruptive.

How do charged amino acid residues affect alpha helix stability?

Charged amino acid residues can affect alpha helix stability through electrostatic repulsion. When charged residues are adjacent to each other, they repel each other, destabilizing the helix structure. For example, polyglutamate and polylysine can lose their helical structure at certain pH levels due to the repulsion between similarly charged residues, leading to a random coil conformation.

What role does steric hindrance play in alpha helix disruption?

Steric hindrance occurs when bulky amino acid residues are adjacent to each other in the alpha helix. These large side chains can physically interfere with each other, preventing the proper alignment and hydrogen bonding necessary for helix formation. This destabilization can lead to the disruption of the alpha helix structure, favoring other conformations.