State of the Science

Water, the medium necessary for protein folding.

Understanding water at the molecular level

Water is essential in cell biology – it possesses unique properties that make life possible. Three key properties of water are particularly relevant and are described in the scientific literature:

The ability to absorb specific electromagnetic energies
Die Bildung kohärenter Domänen
The alteration of order (entropy) at surfaces

When water molecules absorb certain electromagnetic energies, coherent domains form; these are tiny regions of
increased order (low entropy). These are rapidly transmitted to the surrounding
water molecules, similar to a wave in a stadium. When these domains encounter a surface, they form a thin layer of ordered water molecules, the
so-called exclusion zone (EZ). Without a constant supply of coherent domains, these EZs are short-lived and cannot be stored. However, they play a crucial role in biological processes.

According to the quantum electrodynamics (QED) theory of water (developed by Del Giudice, Preparata, and Vitiello), coherent domains (CDs) form in liquid water under the influence of electromagnetic fields (EMF).

The generation of these domains does not occur through a simple chemical reaction, but rather through physical processes that influence molecular arrangement and vibration. Coherent domains represent a state of increased local order in water, induced by interaction with interfaces and electromagnetic fields. This phenomenon is central to explaining the unique physical properties of water in biological systems.

Key mechanisms for generation

Electromagnetic Fields: Due to its dipole properties, water is highly sensitive to electromagnetic fields. These fields can excite water molecules to align and switch to coherent vibrational states.
Energy Absorption: The interaction of light (especially infrared light) and other forms of energy with liquid water creates these quantum coherent domains, in which the water molecules collectively oscillate between a ground state and an excited state.
Surfaces and Interfaces: Coherent domains are often stabilized at surfaces, such as cell membranes, proteins, or macromolecules in biological systems. At these interfaces, a structured layer (often referred to as “exclusion zone water” or EZ water) forms, which promotes coherent behavior. In this layer, the water molecules are arranged in a highly organized, crystal-like (but liquid) hexagonal lattice structure.
Reduced entropy: This ordered arrangement represents a state of lower entropy. The molecules have fewer degrees of freedom and vibrate synchronously (coherently).

The role of water in protein folding

In cell biology, the properties of water—energy absorption, the formation of coherent domains, and surface order—are fundamental to protein folding. The process begins with the release of specific, absorbable electromagnetic energy by excited free radicals. This energy is absorbed by the surrounding water molecules and forms coherent domains, which create a thin layer of more highly ordered water molecules on the surface of unfolded proteins. Subsequently, the entropy exchange crucial for protein folding takes place. Unfolded proteins exist in a disordered state (high entropy). To fold into a more ordered protein, the unfolded protein must transition to an ordered state (low entropy). The water relinquishes its order, the proteins gain order, fold, and become structured and functional.

The process of protein folding

Protein folding is a thermodynamic process controlled by a change in entropy between the protein and the thin layer of ordered water surrounding it. Functional proteins are formed when an unfolded amino acid chain transitions from a state of low order (high entropy) to a state of high order (low entropy).

Ordered water, also called exclusion zone water (EZ water), has low entropy because its molecules are highly structured. In contrast, an unfolded amino acid chain has high entropy because it is disordered.

When an unfolded amino acid chain is surrounded by ordered water with low entropy, a change in entropy can occur. This transition causes the order in the water layers around the protein to decrease, allowing the protein to fold into its highly ordered, functional 3D structure. This mechanism demonstrates how crucial the correct water structure is for efficient protein folding and, consequently, for cell function.

Protein folding is a complex thermodynamic process that requires and involves an entropy change (a change in entropy). The process is a fascinating example of the interplay between entropy and enthalpy in a biological system.

The net entropy change during protein folding is negative, meaning the system becomes more ordered. This seems to contradict the Second Law of Thermodynamics, which states that entropy must increase in an isolated system. However, protein folding is not an isolated system; it takes place in aqueous solution.

The role of entropy in protein folding

The overall process is described by the Gibbs-Helmholtz criterion:

ΔG = ΔH – TΔS

For folding to occur spontaneously, the Gibbs free energy (ΔG) must be negative.

The entropy contribution (ΔS) can be divided into two main components:

Entropy of the polypeptide backbone (negative)
- Unfolded state: The unfolded protein (the random coil conformation) has a very high conformational entropy because many different structures are possible.
- Folded state: The folded, native protein adopts a specific, highly ordered, and rigid three-dimensional structure.
- Net effect: The reduction of possible conformations leads to a significant

Entropy of water (positive and crucial): This is the crucial factor that enables folding.
- Unfolded state: The hydrophobic (water-repellent) side chains of the unfolded protein are exposed to water. The water reacts by forming ordered cage structures, called cages or clathrates, around these hydrophobic residues. This greatly reduces the entropy of the water.
- Folded state: During folding, the hydrophobic side chains move into the interior of the protein, away from the water (hydrophobic effect). The ordered water cages dissolve, and the water molecules are released into their free, disordered state.
- Net effect: The release of these water molecules leads to a significant reduction in the entropy of the protein.

Conclusion

The total entropy change (ΔS_{_total}) for the system (protein + water) is composed of the negative contribution of the protein and the positive contribution of the water.

ΔS_total = ΔS_protein+ ΔS_water

The positive entropy gain from the solution water is usually large enough to offset or even exceed the negative entropy loss of the protein.

The hydrophobic effect is therefore the main driving force for protein folding, driven by the entropy gain of the water.

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