What is the relationship between the genetic code and protein folding?

Asked by anonymous


Basically, the genetic code (that is, DNA) dictates the sequence of amino acids that makes up a protein, with amino acids being the building blocks of the final protein. These amino acids then determine the folded shape of the protein by the way they make bonds and interact with neighboring amino acids, something that is dictated by the sequence in which they’re chained. In this way, the genetic code determines protein folding. However, it’s actually a little more complicated than that because there are many other factors that affect protein folding.

During the preliminary stage of protein synthesis, the gene transcript itself (the messenger RNA, mRNA) is edited and sections of RNA can be removed and added. Even before transcription of mRNA, there are factors that can regulate the expression of particular parts of the genetic code, meaning that there are proteins that can turn on or turn off gene expression. The DNA sequence is transcribed into mRNA by RNA polymerase and then translated by a ribosome into a chain of amino acids. Each codon, a unit of three bases in the genetic code, ends up corresponding to one amino acid. Of course, both transcription and translation are also imperfect processes where mistakes can often be made, and these will of course affect the end result, although such changes can have little or no impact on the overall shape of a protein.

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The ultimate shape of a protein comes from the fact that it “wants” to be in its lowest energy state, which means that the shape it takes needs to require as little energy input as possible. Immediately after a protein is translated, or synthesized, in a ribosome, it spontaneously twists and condenses to form the most energetically stable shape. Each amino acid along the chain helps to determine how it folds based on the properties of the amino acid side-chains. These side-chains are polar or non-polar, acidic or alkaline, etc., and all have different chemical properties that will influence folding. Protein structures develop in different stages of increasing complexity. A freshly synthesized, unfolded and unmodified protein has what is referred to as a primary structure. Secondary structures, such as alpha helices and beta pleated sheets, develop from amino acids side-chains interacting and forming hydrogen bonds with each other. Tertiary structure describes when all the beta sheets and alpha helices condense into the overall three-dimensional structure of the protein. Some proteins go on to bind with other proteins and gain an additional quaternary structure.

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Most of these properties come from the pattern of hydrophilic (polar) and hydrophobic (nonpolar) amino acids. Generally speaking, the most stable structure is going to be the one that folds hydrophobic acids away from the solution the protein is in, hiding them away on the inside of the structure and closing them off with hydrogen bonds while wrapping its hydrophilic acids around its exterior where they can interact with the solution. Amino acids that can form hydrogen bonds with others also influence much of the protein folding. In that sense, the amino acid sequence is what causes the protein to fold the way it does, and that sequence is what the genetic code dictates.

Other factors can also influence the formation of protein structures. For instance, the environment that the folding process takes place in has a huge effect on the final structure. Most protein synthesis takes place in cytoplasm of the cell, which is almost entirely water, but the pH, the temperature, and the presence of other enzymes interacting with the protein as it develops can change its structure. This is also one of the reasons why proteins may form “incorrectly,” or differently than they usually do. Since a protein’s chemical function is based almost completely on its shape, abnormal biological protein folding can result in a protein that is useless or harmful to the body that created it.

Additionally, some proteins require the assistance of other proteins to fold them because their ability to randomly reach the most stable state has too high of an activation energy. This means that the energy required for them to fold into their most stable form is too great to accomplish by random folding alone and these proteins require some assistance from enzymes called chaperone proteins. Without chaperones, some proteins form improperly. But for most proteins, the folding process occurs randomly and spontaneously, and the main determinant of folded structure is the primary amino acid sequence dictated by the genetic code.

Sources and more information:

The Science Behind Foldit, a game used to apply human intuitive skills to protein folding simulation

Nature Publishing Group’s Horizon Symposia’s page on protein folding by Joachim Pietzsch

A video on the process of transcription and translation

A longer video from Crash Course about protein synthesis

Answered by Lauren W., Expert Leader

Edited by Carrie K.

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