Life & death between the double helix & the cross-β sheet

The DNA double helix is probably the most famous structure in the world. Since its discovery in 1953; it became an icon for the molecular basis of life, featured in arts and architecture as a symbol of science's triumph and beauty. However, it is less known that another double-stranded structure is involved in devastating diseases such as Alzheimer's, Parkinson's, and mad cow diseases; the cross-β structure. This structure forms the basis of all amyloids and prions. 

Both the double helix and the cross-β structures are said to have the capacity to replicate and transmit biological information. But how similar/different are these two double-stranded structures? Why one of them encodes life while the other causes death?

The double-helix/cross-β is the relevant comparison when we want to study the question of whether amyloids/prions can self-replicate and what are their functions in biology and disease. We should not be discussing the amyloid superstructures (the so-called strains- ribbons, twisted ribbons, fibrils, nanotubes, etc.), which are just different associations of different cross-β protofilaments. Instead, the relevant discussion should be about the basic cross-β architecture of the protofilament and how it compares to the information-bearing double-stranded helix of DNA, as demonstrated in Fig. 1 and Table1.

Figure 1 illustrates the basic structural differences between the DNA double helix and the cross-β structure of amyloid protofilaments.

Fig. 1. A. DNA x-ray diffraction (the original picture from Rosalind Franklin) indicating a double-helical structure. B. Amyloid x-ray diffraction indicating a cross β structure of the protofilament subunits that assemble into different fibrillar shapes, or so-called "strains".

 Table 1. illustrates the fundamental differences between the two structural architectures: 

Double helix	Cross-β Sheet
Helical	β-sheet
Hydrated	Dry
Soluble	Insoluble
Pairing mechanism (A:T, C:G), ensures replication with fidelity	No specific pairing mechanism
Linear triplet code	No code
Specific sequence	Generic fibrillar structure
Open (major & minor grooves for protein binding)	Closed (no specific protein binding)
Can unwind	Cannot unwind
Dedicated machinery for unwinding, replication & transcription	None
Low sensitivity to extrinsic factors (concentration, temperature, pH, surface catalysts)	High sensitivity to extrinsic factors (concentration, temperature, pH, surface catalysts)
Nucleation Independent (Active process that requires ATP)	Nucleation Dependent (Passive process dependent on the total free-energy of the system)
Organized in well-defined chromatin architecture, up to chromosomes	Stochastic protofilament stacking depending on microenvironmental conditions

Based on the comparison of properties in table 1, it becomes clear why life chose nucleic acids for information and proteins for structure. With DNA, life’s information can be stably encoded then translated with fidelity. It's based on active ATP-dependent processes with an army of dedicated protein machinery that can bind, unwind, replicate and transcribe DNA based on fixed molecular codes (Video 1). DNA replication is NOT dependent on nucleation and elongation, which are the mechanisms of creating amyloids. Nucleation is too stochastic as it's dependent on extrinsic microenvironmental factors such as pH, concentration, and even agitation. These factors cannot be encoded in the structure, and hence, cannot be faithfully replicated.  Importantly, amyloid aggregation can be triggered by surfaces via the well-known physical mechanism of heterogeneous nucleation in absence of protein seeds & with no conformational templating.

Video 1. The elegant mechanisms and machinery of DNA replication.

That's probably why the cross-β structure is more involved in death than life. It's anhydrous, flat, with no grooves for enzymatic binding, too stable to unwind, too hydrophobic to dissolve, bears no code, and sticks together in weird shapes based on microenvironmental factors such as pH, concentration, or agitation. The properties of the cross-β architecture are not only different from DNA, but they are also the opposite, and that is why the term amyloid/prion "strain" is a huge misnomer. The word "strain" in the traditional biological sense refers to a defined genetic variant of a microorganism. The cross-β architecture, which bears no code and associates into different shapes or polymorphs based on environmental conditions, cannot hold or transmit biological information in any way remotely similar to biological strains. Nucleation and physical association has nothing to do with how life operates, and we should not be mixing the terms. 

Why is this important? Who cares about strain or no strain? 
These definitions are important because a. science is continuous and b. our practical solutions depend on how we conceptualize the problem, science works when it's accurate.   

a. Science is a continuous process, we cannot just ignore the previous concepts established regarding the prerequisites for a molecule to carry and transmit biological information and ignore physical principles such as nucleation and phase transition, which are necessary & sufficient to completely explain the amyloid phenomenon. This is how the pioneers of physical chemistry and molecular biology have worked, and this is how we should keep working. You can watch Sydney Brenner describing the principles that lead to molecular biology here. 

b. We pride ourselves that science works, but science needs accurate conceptual frameworks, good theories and hypotheses together with good experiments. If the theory is wrong, no matter how many billions you throw at it, it won't work. This has been very clear in the field of neurodegenerative diseases, where the main theory of viral-like amyloids that are toxic to cells failed to produce any useful therapeutics. 

It's would be much more useful to view amyloids as they are, just a process of aberrant crystallization (phase transition) that is triggered in the nervous system by seeds or microbes or aberrant lipids, causing proteins to lose their solubility, conformation, and ultimately their function, resulting in cell death. More discussion about this in our review here, and blogpost about loss-of-function here, and in this video debate.