RNA molecules continually change shape. According to Hashim M. Al-Hashimi, professor of chemistry and biophysics at the University of Michigan, scientists hypothesized that these structural changes are the result of complex chemical interactions that occur when RNA binds with proteins and drug molecules. Al-Hashimi and his team believe that the changes might be simpler than previously thought. They discovered that the changes in the three-dimensional structure of RNA molecules are governed by simple and consistent geometric rules.
"RNA is a very floppy molecule that often functions by binding to something else and then radically changing shape," said Al-Hashimi in a press release. “[Therefore] you can't really define it as having a single structure. It has many possible orientations, and different orientations are stabilized under different conditions, such as the presence of particular drug molecules."
Scientists are coming to understand RNA’s role in human disease, prompting more studies on its interactions. According to Al-Hashimi, the RNA’s shape changes control processes like gene expression. Researchers could control certain cellular processes if they could manipulate RNA’s shape-shifting, which results from interactions with other molecules.
In previous research, Al-Hashimi’s team demonstrated that RNA shape changes are predictable. They observed that proteins and drug molecules wait for RNA to assume a specific shape before binding. This is why it appears that RNA changes shape when it binds to a new molecule. For their most recent research, Al-Hashimi’s team set out to determine what forces control the predictable shape changes of RNA.
"Your body has a specific shape that changes predictably when you are walking or when you are catching a ball; we want to be able to understand these anatomical rules in RNA," said Al-Hashimi."RNA is very similar to the human body in its construction, in that it's made up of limbs that are connected at joints." RNA can be single stranded or double stranded. In their recent paper, the researchers describe these RNA limbs as the strands of the double helix, with the junctions between strands as flexible joints comparable to the structure and function of the human wrist or elbow.
"We wondered if the junctions themselves might provide the definition [for why RNA changes shape]," said Al-Hashimi "If you look at your arm, you'll notice that you can't move it, relative to your shoulder, in just any way; it's confined to a certain pathway because of the joint's geometry. We wondered if the same thing might be true of RNA."
To investigate this hypothesis, the researchers analyzed a database of RNA structures and discovered that all structures with two strands linked by a junction called a trinucleotide bulge assumed the same shape. Through multiple tests, the researchers found the motion of RNA’s strands to be dependent on the structural features of the junction.
The researchers then analyzed the shape changes that facilitate drug molecules binding with RNA. Al-Hashimi wanted to know why some RNA molecules assume relatively straight shapes after interacting with specific drugs, while others assumed bent or curved structures. Al-Hashimi’s team evaluated changes in the shape of the RNA after exposure to a series of aminoglycosides, antibiotics that target RNA. The researchers found that the biggest aminoglycosides caused RNA to freeze in bent positions. Small aminoglycosides caused RNA to freeze in a straight position. According to the researchers, this occurred because the aminoglycoside molecule inserts itself into the RNA molecule between the two strands, acting like a wedge that forces the strands apart. This simple geometric concept is responsible for changing the shape of the RNA strands.
"This will make it possible to gain insights into the 3-D shapes of RNA structures that are too large or complicated to be visualized by experimental techniques such as X-ray crystallography and NMR spectroscopy," said Al-Hashimi.
Funding was provided by the National Institutes of Health, the National Science Foundation, the W.M. Keck Foundation, the Michigan Economic Development Corporation, and the Michigan Technology Tri-Corridor. The paper, “Topology links RNA secondary structure with global conformation, dynamics, and adaptation,” was published online Jan. 8, on Science.