Once the polypeptide is complete, it must fold into the shape that is required for the new protein to function. See the example below [figure 4-50]. Note the unfolded polypeptide at the top, and below it, how this small protein might fold. Also note that the protein will fold in such a way that some of the surfaces face outwards and interact with water, whereas others are protected from water in the interior of the mass.
Long polypeptide chains are very flexible and can in principle fold in an enormous number of ways. 
Most of the single covalent bonds that link the subunits of a macro-molecule allow rotation of the atoms that they join; thus the polymer chain has great flexibility. In principle, this allows a single-chain macro-molecule to adopt an almost unlimited number of shapes as the polymer chain writhes and rotates under the influence of random thermal energy. However, the shapes of most biological macro-molecules are highly constrained because of weaker, non-covalent bonds that form between different parts of the molecule…In many cases, non-covalent interactions ensure that the polymer chain preferentially adopts one particular conformation, determined by the linear sequence of monomers in the chain. Most protein molecules and many of the RNA molecules found in cells fold tightly into a highly preferred conformation in this way. These unique conformations – shaped by billions of years of evolution – determine the chemistry and activity of these macro-molecules and dictate their interactions with other biological molecules. [p. 61]
Imagine amino acids as various configurations of tinker toys strung along like a polypeptide, say a thousand amino acids long, the typical size of a protein. Then imagine, with the ability of the molecules in the chain capable of rotating at several joints – just like they do in tinker toys – to fold and twist and re-connect in countless ways.
It’s critical to note that the configuration of a protein is essential to its function. Also that the same protein, when folded properly, will always fold in the same way.
Although it is possible that a protein can fold into its correct conformation without outside help, protein folding in a living cell is generally assisted by a large set of special proteins called chaperone proteins. [p. 123]
The text goes on to assert that the final three-dimensional shape of the protein is still specified by its amino acid sequence and that chaperones merely make the folding process more efficient and reliable. [p. 123]
This glosses over the fact that every protein is capable of folding incorrectly (see left hand example below in figure 4.8). This makes sense because most proteins can fold in a gazillion different ways. As shone below, most proteins require chaperon proteins to fold into the correct configuration.
In some cases, the chaperones are quite sophisticated themselves. See below [figure 4-9].
In the example above, not only is a separate chamber required, but additional energy as well. The cell goes to a great deal of trouble to configure the proteins correctly.
Once the protein has been folded correctly, many of them require cofactors and co-proteins prior to becoming functional (see figure 7-45 below).
The process to create proteins, from DNA coding to mRNA transcription to mRNA splicing to mRNA export to mRNA translation (with input from various tRNAs) to protein folding and addition of co-factors, is complex, deliberate, intentional and controlled. There is nothing random or accidental about their creation. This doesn’t happen without the specific context of a living cell
Proteins are by far the most structurally complex and functionally sophisticated molecules known. [p. 119]
Proteins are the main building blocks from which cells are assembled. And they constitute most of the cell’s dry mass. In addition to providing the cell with shape and structure, proteins also execute nearly all of its myriad functions. [p. 117]
There are about 100,000 different known proteins. [p. 124] Figure 4-10 below provides a small sampling of representative proteins, along with their relative size and shape.
The creation and utilization of proteins within the cell is deliberate and closely managed:
Inside the cell, most proteins and enzymes are regulated in a coordinated fashion so the cell can maintain itself in an optimal state, producing only those molecules it requires to thrive under current conditions. By coordinating not only when – and how vigorously – proteins perform, but also where in the cell they act, the cell ensures that it does not deplete its energy reserves, by accumulating molecules it does not need or waste its stockpiles of critical substrates. [p. 149]
The simple fact that these molecules are ‘regulated’ and used in a ‘coordinated’ fashion suggests that something more than known physical and chemical forces are involved. The text elaborates:
The regulation of protein activity occurs at many levels. At the most fundamental level, the cell controls the amount of each protein it contains. It can do so by controlling the expression of the gene that encodes that protein. It can also regulate the rate at which the protein is degraded. The cell also controls protein activities by confining the participating proteins to particular sub-cellular compartments. Some of the compartments are enclosed by membranes; others are created by the proteins that are drawn there. Finally, the activity of an individual protein can be rapidly adjusted at the level of the protein itself. [p. 149]
Once a protein is created, it needs to find its way to the proper location. What follows includes more detail of how the cell deploys proteins from one place to another within the cell.
One way that proteins made in the cytosol are dispatched to different locations in the cell is through specific address labels contained in their amino acid sequence. [p. 500]
Given that the amino acid sequence determines the type of protein and how it is folded, would this labeling restrict a specific protein to a single target location within a specific cell?
Apparently so, as once at the correct address, the protein enters either the membrane or the interior lumen of its designated organelle. [p. 500] But how does the cell ‘know’ what kind of protein is required where? Recall that the cell is significantly larger than any particular element within it. There isn’t a brain or nervous system to sense conditions from one side of the cell to the other, let alone control internal conditions. Or is there?
Transporting proteins is another complex and mysterious process. For instance:
As a protein passes from one compartment to another, it is monitored to check that it has folded properly and assembled with its appropriate partners, so that only correctly built proteins make it to the cell surface. Incorrect assemblies, which are often in the majority, are degraded inside the cell. Quality, it seems, is more important than economy when it comes to the production and transport of proteins via the secretory pathway. [p. 516]
Where in this process is the intelligence that determines whether or not a protein is folding/configured correctly? In DNA and RNA we have the coding and translations that configure the protein in the first place, so we understand the relationship there, but how does a distant compartment maintain the understanding of what a proper protein looks like? And the compartment can’t recognize just one kind of protein: thousands of proteins exist within the cell at any one time, and any gateway needs to accommodate several types of proteins, each of them quite different. The text provides the following explanation [figure 15-25]:
More on the ER [endoplasmic reticulum] lumen in a moment, but first consider what it takes to perform the recognition that is described in the narrative in figure 15-25. The complexity of the functions described is fantastic.
As a specific example of import, consider how a protein created in the cytosol transitions into the mitochondria:
Human cells contain 1000-2000 mitochondria, all of them requiring proteins to function properly. How do the correct number and type of proteins created in the cytosol reach each one of them? How does the sending authority (one that plans and distributes proteins) ensure that each of the thousand mitochondria get what they need? In other words, how does a particular mitochonrian signal that it needs one thing, and not another? This is important because creating proteins takes precious energy and resources, and the cell can ill afford to be wasteful. And even if such signaling takes place, how does the needed protein find a particular mitochondrian? They are all just floating around randomly within the cytosol. No streets, no addresses.
One way the cell manages what proteins are produced where is through two classes of ribosomes:
There are…two separate populations of ribosomes in the cytosol. Membrane-bound ribosomes are attached to the cytosolic side of the ER membrane (and outer nuclear membrane) and are making proteins that are being translocated into the ER [endoplasmic reticulum]. Free ribosomes are unattached to any membrane and are making all the other proteins encoded by the nuclear DNA. Membrane-bound ribosomes are free ribosomes are structurally and functionally identical; they differ only in the proteins they are making at any given time. When a ribosome happens to be making a protein with an ER signal sequence, the signal sequence directs [my emphasis] the ribosome to the ER membrane. [p. 508]
Once again, we encounter casual language about something that seems quite mysterious. Ribosomes do not have legs or fins, so how does it get to the ER membrane once it gets ‘directed’? Or if the ribosome is already attached to the ER membrane, how does the mRNA with the proper signal sequence ‘know’ which ribosome that it seeks?
The endoplasmic reticulum (ER) is the most extensive membrane system in a eukaryotic cell. [p. 507] All proteins destined for other organelles (other than the nucleus, chloroplasts or mitochondria) or the cell surface first enter the ER:
Entry into the ER lumen or membrane is usually only the first step on the pathway to another destination. [p. 511]
Entry into the ER is no small thing:
The ER lumen is only the first stop:
That destination (after the ER lumen), initially at least, is generally the Golgi apparatus; there, proteins and lipids are modified and sorted for shipment to other sites. [p. 511]
The Golgi apparatus is an amazing organelle, as it can ‘modify’ and ‘sort’ these various molecules before transport to their final location.
Transport from the ER to the Golgi apparatus – and from the Golgi apparatus to other compartments of the endomembrane system – is carried out by the continual budding and fusion of transport vesicles…Together, these pathways thus provide routes of communication between the interior of the cell and its surroundings. [p. 511]
This entire transport process is amazing, and worth some detailed attention. Getting the proteins to the Golgi apparatus, and later from the Golgi apparatus to the rest of the cell, requires vesicular transport. This entails a cargo wrapped in a special protein skin that gets transported from one place in the cell to another, or in some cases to the cell membrane. See figure 15-18 below: