I read in many journals that amino acids with branched and large aromatic R-groups have higher beta pleated sheet propensities. However, none really go in depth into the significance or reasoning behind this finding. I have made an educated guess based on my findings on alpha helix propensities:

In alpha helices, branched and aromatic R-groups are not favored as the g+ and g- isomers can extend into the helix and interfere with the hydrogen bonding. In beta pleated sheets, however, the R-groups are pointed perpendicular to the hydrogen bonds, and even large R-groups like that of phenylalanine or tryptophan will not able to reach the site of hydrogen bonding. Coupled with the fact that smaller amino acids will rather be more tightly bound to each other (so they prefer helices, e.g. collagen helix, alpha helix, save space, amide hydrogens and carbonyl oxygens closer together), larger amino acids therefore favor formation of beta pleated sheets.

I need a few key pieces of info to really accept my own explanation (if it is correct) as factual. First, I will need proof that beta pleated sheets are more structurally rigid than alpha helices (or else, smaller R-groups like that of alanine and cysteine will also prefer beta pleated sheets). I also kinda want to see the structure of beta pleated sheets with large R-groups to further ground the thought in my head, as I can't really see how R-groups like valine (heavily branched) will not affect hydrogen bonding. As an example, I attach one that I found for alpha helices. valine in an alpha helix

  • $\begingroup$ are you familiar with visualization software such as Pymol or VMD? $\endgroup$ – Roni Saiba Nov 22 '20 at 18:51

This table is from the Wikipedia page for α-helix: Amino acid propensity for α-helix

As you can see aromatics are not the worst offenders. In fact, barring proline (whose backbone torsion angles are unsuited to helices), Gly is the worst offender. A likely reason for this is Gly being too flexible i.e. its small side chain H allows it to adopt backbone torsion angles unsuited for α-helix.

As another example let's look at silk, an extended anti parallel β-sheet structure, from libretexts. silk β-sheet

As you can see, the small side chains of Ala and Gly in fact allows the β-strands to come close enough to form backbone hydrogen bonds. In fact, from the same reference I quote - "Unlike the α helix, though, the side chains are squeezed rather close together in a pleated-sheet arrangement. In consequence very bulky side chains make the structure unstable."

So it is not entirely true that aromatic amino acids prefer pleated β-sheets.

So what are we missing? We are missing the chemical environment in which the the amino acid residues are placed. Remember, most of the propensity charts we look at are average propensities across known protein structures. In a specific protein, its specific chemical context can radically change the secondary structure propensities.

  • $\begingroup$ I am aware of the effects of proline and glycine on secondary protein structures, but didn't find it relevant to the question, but thanks for further clarifying it anyways. Your example of silk is really insightful as well. However, I am still wondering why the aromatic residues have a higher average propensity (through various chemical contexts, like you mentioned); at least, relatively higher than smaller residues like on alanine, glutamate etc. $\endgroup$ – chematwork Nov 24 '20 at 5:04
  • $\begingroup$ Also, I am confused when you say that alanine and glycine allow the beta-pleated sheets to come close enough to form backbone hydrogen bonds. Aren't backbone hydrogen bonds formed despite the residues (excluding proline)? Do you mean the hydrogen bonds will be stronger as they are closer together? In antiparallel beta sheets the amide hydrogen and carbonyl oxygen are pointing directly at each other, so I doubt they will not form bonds even if there is more space in between. $\endgroup$ – chematwork Nov 24 '20 at 5:09
  • $\begingroup$ @chematwork The strength of a hydrogen bond depends on the distance between the bond donor and acceptor, electronegativities of the atoms and the angle donor--H--acceptor. So if you have bulky side chain residues in beta sheets (e.g. a benzene ring is around 4 A in length) you can see that they will weaken hydrogen bonds as the distances between the bond donor and acceptor will increase. $\endgroup$ – Roni Saiba Nov 24 '20 at 11:17
  • $\begingroup$ @chematwork — This answer is far better than yours because it exposes the fundamental fallacy of “the average beta sheet” of your question. The average human being has one ovary and one testicle. Alpha helices do allow certain general principles, but the variety of conformations of beta-sheets in proteins, and the variety of their environments preclude all but the most superficial statements. When few structures were known, this sort of thing was all one could say. Fifty years have passed since then. $\endgroup$ – David Nov 25 '20 at 19:49
  • $\begingroup$ @David I checked the beta sheet propensities of aromatic side chains and while they have high average propensities, I seriously doubt a polypeptide of only aromatic side chains will show a tendency to form a beta sheet. Sadly I don't have enough expertise to run MD simulations to check this. $\endgroup$ – Roni Saiba Nov 26 '20 at 6:23

I have found this image on Biology LibreTexts, and they have answered my question. Like I suspected, the large residues will mainly project out of the beta pleated sheet and will not interfere much with the backbone hydrogen bonds. In alpha helices, however, the branched and aromatic residues are still able to project into the helix (as they are not pointing completely outwards) and disrupt the bonds.

To better visualize it, imagine a foam cylinder and toothpicks poking out of it at an angle. Now imagine the toothpick branches out in all directions (to simulate rotamers). It will poke the cylinder again. Now imagine a flat foam board with toothpicks sticking out of it up and down at an angle. Even if it branches out, it will not ever poke the board again unless it branches backwards (impossible for residues, I reckon).

In beta pleated sheets, aromatic interactions between two aromatic rings might further stabilize the structure. In alpha helices, the residues are pointing away from the helix and therefore not that close to each other; but in beta pleated sheets, they are close enough to interact.

I have also found a viable reason to why beta pleated sheets are supposedly more "rigid" than most other secondary structures. Alpha pleated sheets are really compact and only involve one peptide chain, whereas beta pleated sheets are less compact and include two or more peptide chains, limiting the movement and decreasing the overall entropy.

If you still have trouble visualizing, visit the Biology LibreTexts page and look at their splendid diagrams modelling the secondary structures. They really helped me in understanding it. It is quite elusive, so I'll link it here

Propensities of amino acids to form secondary structures


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