Why do hydrogen bonds between atoms of the polypeptide backbone, form both helix and pleated structures, instead of only one structural type?

Question

Proteins have segments of their polypeptide chain/chains that can be repeatedly coiled or folded into helix and pleated structures, respectively. This is due to hydrogen bonds between partially charged oxygen and hydrogen atoms in the repetitive polypeptide backbone (which excludes the amino acid side chains).

My guess is that one structure (either a helix or pleated structure) is lower in potential energy compared to the other (because one structure likely maximises the number of hydrogen bonds that can form, compared to the other), which begs the question, why do both structures form, if they are largely a result of hydrogen bonds in the polypeptide backbone, rather than only one structure forming?

Is it a result of both hydrogen bonds in the polypeptide backbone, and interactions between amino acid side chains?

My own attempt at answering the question:

Intuitively, I believe the terms 'secondary' and 'tertiary' structure are misleading. My reasoning is that, it does not make sense to say that hydrogen bonds between the atoms of different amino acids in a polypeptide backbone, bring separate amino acids closer together, before interactions between amino acid side chains (R groups) occur (especially since some of these interactions between R groups are hydrogen bonds themselves).

I assume, the previous statement can be valid stated vice versa, i.e., that interactions between amino acid side chains bring separate amino acids closer together, before hydrogen bonding can occur between the atoms of different amino acids.

Ultimately, if this is the case in reality, I would expect both H bonds and AA side chain bonds to occur, effectively, simultaneously, blurring the distinctions that have been established by humans.

Answer 1

Particular protein structures arise because of a potentially very complex interplay of interactions within a chain, with other chains (from other subunits in a multimeric protein or from chaperones or other biomolecules) and with the solvent which includes water, lipids, ions, small molecules. All of these contribute to the adoption of a final fold but also to that of intermediates on the folding pathway. Sometimes the final fold is not "triggered" until an apo structure is further processed or associates with a target, for instance by cleavage (insulin), cross-linking (insulin), binding of a cofactor (azurin) or self-association (amyloid).

Generally the most important factors determining the secondary structure are the balance of hydrogen bonds, interactions between the hydrophilic sidechains of polar residues with the solvent, and hydrophobic interactions that result in burial of hydrophobic sidechains in the protein interior. The balance between specific interactions is generally very finely tuned so that only a desired structure is adopted, such as a helix, a beta sheet or a turn between secondary structure elements. Sometimes folding is hierarchical, with secondary structure elements forming more rapidly (for instance helices) before associating into higher-order tertiary structures (motifs). Sometimes cooperative interactions between secondary structure elements is required (for instance in sheets). Some aminoacids are bulky (tryptophan) and cannot be accommodated except in particular structures because of steric clashes. Some aminoacids have structural constraints and are only found in particular sites such as turns or unusual secondary structures (proline). Some residues have a low propensity to be found in helices (glycine, proline) because of entropic penalties or constrained backbone dihedral angles.

Because the many individual interactions can be weak, proteins sometimes are assisted during folding by other proteins (chaperones) that encourage desired interactions and discourage unwanted ones. The folding history and tertiary interactions can decide the final fold, such that the protein undersamples its possible conformational realm before acquiring its functional form.

Answer 2

Proteins have segments of their polypeptide chain/chains that can be repeatedly coiled or folded into helix and pleated structures, respectively. This is due to hydrogen bonds between partially charged oxygen and hydrogen atoms in the repetitive polypeptide backbone (which excludes the amino acid side chains).

Hydrogen bonds alone can't explain the structure of proteins because making hydrogen bonds with water is just as good. When you look at the overall picture (entropy and enthalpy of folding in the presence of water), it turns out the helices and sheets do occur frequently in folded structures.

My guess is that one structure (either a helix or pleated structure) is lower in potential energy compared to the other (because one structure likely maximises the number of hydrogen bonds that can form, compared to the other), which begs the question, why do both structures form, if they are largely a result of hydrogen bonds in the polypeptide backbone, rather than only one structure forming?

As stated above, potential energy alone is not sufficient to rationalize protein conformation. In the end, it is Gibbs energy that decides, so enthalpy and entropy. Also, you have to consider effects on the protein and the solvent, not just the protein. This becomes clear when you add other solvents, or place a protein in vacuum, where it often denatures.

Is it a result of both hydrogen bonds in the polypeptide backbone, and interactions between amino acid side chains?

The side chains are important, also for the energy of the main chain conformations. For example, the alpha helical conformation is unusual for amino acids with a branched side chain at the beta position (e.g. valine or threonine).

Intuitively, I believe the terms 'secondary' and 'tertiary' structure are misleading.

If you think of them as hierarchy of structure (from local to larger and larger scale), they make more sense than if you interpret them as an order of folding. In the biological context, the N-terminal end of a protein sometimes folds before the C-terminal part is even synthesized (so parts of the tertiary structure form before the primary structure is fully formed).

Ultimately, if this is the case in reality, I would expect both H bonds and AA side chain bonds to occur, effectively, simultaneously, blurring the distinctions that have been established by humans.

Yes, secondary and tertiary structure form mostly concurrently after formation of a molten globule (i.e. hydrophobic side chains starting to cluster). It is thought that the last feature that forms are the disulfide bridges, as shown in the famous Anfinsen set of experiments.

Answer 3

I imagine this is largely determined by function. In a protein such as bacteriorhodopsin there are several parallel helices which hold the protein as a fairly rigid structure with a channel down the middle, between the helices, where ions are transported. The rhodopsin chromophore acts as a switch for ion transport and sits in the middle of this channel. To function the structure has the be help rigidly because the isomerising chromophore pushes against a helix to open the ion channel. The LHII protein of photosynthetic bacteria has many helices arranges in a ring with each holding chlorophylls and a xanthophyll. These are held exactly in place so that efficient energy transfer around the ring of pigments so formed is efficient. By contrast, the protein I27 is part of the muscle protein titin and has beta sheets that can extend and contract under the action of force, and can extend reversibly to a certain limit without unfolding, so that the muscle can itself work. (btw All these structure are known from x-ray crystallography and easily found using Wikipedia).

These examples given do give some clues as to why there are two types of structures. However, things are never so simple, the protein in the eye's lens, crystallin, is almost all beta sheet and serves to prevent uv damage, such as formation of cataracts, by dumping the uv energy via tryptophan and cysteine residues. So there seems to be no clear cut answer after all.