Molecular Mind in Cellular Motors 3: Disordered Dancing Molecules Allow for Infinite Agility and Creativity

Since DNA’s discovery, molecular biology had operated on reassuring assumptions: every protein folds into one precise, stable shape; shape determines its function; and shape is determined by a sequence of amino acids produced by a sequence of DNA letters. It was a clean idea. The holy grail of bioscience for decades was finding the shapes of proteins and the DNA codes that determine that shape.

It is very difficult to determine the shapes of any protein from the sequence of amino acids and DNA letters. When alternative splicing was discovered, it was clear one DNA code can produce hundreds of different RNAs and amino acid sequences via obscure complex mechanisms.

With an average protein size of 300 amino acids and 20 different types of amino acids, each with different chemical properties, electric charge, and shapes, the factors determining shape are astronomical. There are even more variables, such as hydrogen bonding with water noted in the previous post. For a long time, finding the 3D structure of an average sized protein was far more difficult than any supercomputer could accomplish.  X-rays of crystalline forms of proteins (very different from seeing a living protein) were needed to even guess at the shape.  Now, the most advanced artificial intelligence is able to make good guesses for many protein shapes.

Recently, a strange thing happened. Researchers began discovering proteins that simply did not fold into any single shape at all. These intrinsically disordered proteins—or proteins with some disordered regions—writhe and twist in constant motion, never settling into a shape. Some observers call them dancing molecules. At first, this looked like a problem. How could a molecule without a fixed shape do anything reliable?

The answer overturned the old assumptions entirely. Disordered regions are not defective—they are one of life's most sophisticated inventions, allowing for infinite agility and creativity, like hydrogen bonding in water and non-covalent bonds. Because they flex and wave freely, disordered strands can present many different binding surfaces at different moments, infinitely responsive. A single disordered strand can touch and temporarily bond with dozens of different partner molecules almost instantly, acting as a flexible arm that reaches out in whatever direction is needed.  For example, nuclear pores, which are the vital waterways for large molecules traveling in and out of the nucleus, are lined with proteins that have disordered strands, dangling and dancing in the channel, regulating all molecular movement––grabbing and blocking some molecules and letting others pass.

Perhaps more surprising, disordered proteins are not rare. At least half of all large molecules in living cells contain significant disordered regions. Life, it turns out, does not primarily run on rigid machinery. It runs on flexible, responsive, dancing molecules that can grab, pull, bridge, and release partners in an almost infinite variety of combinations. This is another way that molecules almost instantaneously have vastly sophisticated actions, a pre-requisite for molecular mind in nature.

This led to an equally remarkable finding about RNA. Based on the faulty genetic dogma of Watson and Crick, for almost a century RNA was considered less important than DNA and protein. RNA was considered just a temporary intermediate of less importance. With detailed imaging of RNA in living cells finally available, it has been found that RNA is incredibly flexible in its folding, forming a vast array of changing shapes, some behaving like disordered proteins. There are an almost infinite variety of different types of RNA of all sizes, with a vast array of functions in the cell—at least as many functions as proteins, if not many more.

Intrinsically disordered proteins and RNA, both with their flexible waving strands and multiple binding domains, are among the most important hubs in the cell's molecular intelligence network. Because they can bind many different partners, they act as integrators—collecting signals from multiple sources and combining them into a single output. Many protein transcription factors that control which genes are switched on or off are disordered. Flexibility allows different conformations depending on which partner molecules are present, effectively making context-sensitive decisions about gene expression with almost infinite complexity and responsiveness. A protein can remain partially flexible even when bound to its partner, allowing fine-tuned, graded responses rather than simple on/off switching, a nuance that is a hallmark of intelligent molecular behavior.

The behavior of intrinsically disordered proteins is dominated by interactions with water—complex hydration layers are constantly reorganizing as a strand continually moves. The hydration effects of disordered proteins extend further than those of any folded protein. The constant motion of the protein strands sweeping through the water instantaneously produces hydration layers that extend deep into the cell.  As mentioned in the previous post, these local shifts of water’s structures can at times support the development of water proton wires, which conduct protons a distance for cellular communication or energetic actions.

Also, disordered strands can attract multiple different proteins and RNA, pulling them together and creating a region of greater density of large molecules with less free water.  At a certain density, a unique physical event occurs called a liquid-liquid phase separation. The dense molecules separate from the rest of the cell into a droplet, like a drop of oil in water. It condenses into a singular structure made up of the large molecules functioning as if it is an organelle without membranes. This membrane-less organelle becomes a cellular compartment that allows specialized processes to occur more rapidly. 

Small membrane-less organelles are now found everywhere in the cell and much of the important action of molecular clusters occurs in these droplets.  They can be transient or semi-permanent, such as the nucleolus, a phase separated droplet which produces ribosomes for the cell (there will be more about droplets in future posts). 

The almost infinite flexibility of dancing, swirling molecules attracting all sorts of other molecules for a moment, or a long while, is not chaos. Rather, it is a more sophisticated form of order—one that can sense and respond, adapt and change. It is mind thinking through the movements of molecules. 

We are beginning to see that molecular behavior is not mechanical. It is, in a real sense, the responsive, perceptive, sophisticated, creative behavior of mind in nature.