**is a series of consecutive residues present in a protein. It is associated with (a genetic disorder), such as (HD). In the case of HD, people with more than 36 repeats of Q/glutamine, have a mutant form of the Huntingtin protein (mHt). We don’t fully understand the nature or behavior of this mutant form, however, mHt is known to form protein aggregates, rather than folding into functional forms. These aggregates accumulate with time and eventually interfere with cell function and intercellular communication.
Here is the post:
Quick summary: polyglutamine stretches aggregate due to (a) water being a poor solvent for polyQ and (b) the ability of both the backbone and side chains to form hydrogen bonds, thus contributing energetically to the stability of the aggregate.
Writing that post made me think about the relevance of hydrogen bonding in biological systems. So, this post is about the influence of H-bonding on the energetics of protein folding.
Role of Hydrogen Bonds (H-Bonds):
Hydrogen bonding is one of the most crucial inter and intra molecular interaction in biological systems. Whether it is interaction with solvent or protein folding, energetics is largely driven by hydrogen bonds. The directional nature of these interactions also gives rise to a multitude of spectroscopic properties. paper published in 2000, explored the cooperative nature of hydrogen bonds in peptide systems, thus suggesting that the strength of H-bond should increase (asymptotically) with the extent of H-bond network. This does seems a little intuitive, especially if you are considering the folding of a helix, where the barrier is usually the formation of the first few turns.
Role of H-bonds in amyloids:
- Formation of protein fibrils (stacks of beta sheets) from monomers is a characteristic of a big class of diseases known as protein aggregation diseases [ ]. Structures of some amyloid fibers have been identified , and the process of amyloid formation has been extensively studies [2-4].
- One of the more popular theory is the formation of a nucleus seed for amyloid fibril formation.
Figure 1: cartoon representation of the aggregation process from 
- There have been studies in the last few years, suggesting that the typical nucleus size is 3 to 4 peptides. 
- As this is the minimal size that would not dissociate quickly due to slower diffusion.
- One of the more important finding is the role of H-bonds and its cooperativity in this nucleus size of 3-4 peptides.
- A 2006 study, explored this cooperative H-bond effect in a prion protein, using classical electrostatics and quantum DFT calculations.
- They were able to show that the strength or contribution of H-bonds between peptides increases nonlinearly up to 4 peptides, and then levels off. Thus suggesting the cooperative nature of H-bonds within sheets of a fibril.
Figure 2: (a) one layer of two peptides, (b) 3 peptides stacked one below the other, (c) energy per monomer in a fibril (d) binding energy of a layer to a preexisting fibril. 
- From figure 2d, you can clearly see the leveling off of energy beyond a fiber length of four monomers.
- This effect has also been validated in a polyQ system, where the cooperative effect is shown to have an effect of the geometry of the aggregate 
- Hydrogen bonding, a partially covalent interaction plays a very significant role in determining energetics of protein folding and aggregation.
- The directional nature of the interaction makes modeling the hydrogen bonding energy landscape computationally challenging.
- Empirical molecular mechanics (MM) force fields have much less accuracy and QM electronic structure calculations cannot be adopted to biological systems.
- With the advent of polarizable MM forcefields, there might be hope for more consistency with both electronic structure calculations and other experimental data.