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Physics professor investigates how molecular machines ensure energy efficiency of the cell

by Julia Renner, Environmental Science, 2017

At the intersection of molecular biology and physics lies the potential for greater understanding of one of the most fundamental processes in the cell: the production of proteins by the ribosome, a process that Dr. Paul Whitford, assistant professor of physics at Northeastern University, explains as “essential to all life.” A paper published today in Nature Communications by Whitford and a colleague at Rice University investigates the complex processes that keep protein production efficient and accurate.

“The ribosome is the sole producer of proteins in the cell,” Whitford explains, with a “complexity and large number of moving parts” that makes it “an incredibly challenging system to study.” Protein production in the ribosome requires quick and accurate base-pairing of RNA bases when constructing proteins, and a process this complex requires quality control. Whitford and colleague Jeffery Noel investigated a part of the process, where the ribosome proofreads aminoacyl-tRNA molecules in order to ensure accuracy during protein production.

Selection of tRNA molecules was already known to be extremely efficient and to be highly dependent on proofreading. What was not known is how exactly the ribosome can maintain high efficiency and accuracy. According to a theory known as the Hopfield kinetic proofreading model, the accuracy or fidelity of tRNA selection may be improved by exploiting a multi-step kinetic process, where the ribosome transiently adopts an intermediate kinetic state. Whitford and Noel investigated how the physical properties of the ribosome contribute to reaching this state, thereby enabling successful proofreading.

They focused on a large protein called EF-Tu, and were able to determine that it may play a role in ensuring high accuracy during protein production by making the proofreading step less energy-intensive. “The shape of the ribosome makes it difficult for tRNA molecules to enter” during proofreading, Whitford explains, but “when EF-Tu is present, it is positioned such that the tRNA may easily overcome any obstacle.”

Whitford is three years into a five-year Career Award from the National Science Foundation, and will continue with this line of research, exploring the role that proteins called elongation factors play in the cell. Their research shows promise for the development of new antibiotics that could work by directly targeting protein synthesis in bacterial ribosomes, impeding the ability of bacteria to grow.

“We’re only beginning to scratch the surface,” Whitford says, emphasizing that there’s great room for further exploration: the complex calculations involved in this line of research have only become possible in the past few years, with computing technology like that of the Discovery Cluster at Massachusetts Green High Performance Computing Center. Through this center, Northeastern is taking a leading role developing high-performance computing technology to allow for research into the fascinating world of biological machines.

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