$2 million NIH MIRA grant will support trailblazing research in UMass Amherst lab – BIOENGINEER.ORG

Jianhan Chen, a professor of chemistry and biochemistry and molecular biology at the University of Massachusetts Amherst, received a five-year $ 2 million National Institute of Health (NIH) scholarship to support research in his computer biophysics lab to better understand the role of intrinsically disordered. proteins (IDP) in biology and human diseases.

Jianhan Chen, a professor of chemistry and biochemistry and molecular biology at the University of Massachusetts Amherst, received a five-year $ 2 million National Institute of Health (NIH) scholarship to support research in his computer biophysics lab to better understand the role of intrinsically disordered. proteins (IDP) in biology and human diseases.

The grant is part of the MIRA program of the National Institute of General Medical Sciences, which stands for the Most Researchers Research Award. It is designed to provide highly talented researchers with more flexibility and stability to make important scientific advances in their laboratories.

“The MIRA Award allows us to continue working on several central issues related to the study of disrupted proteins and dynamic interactions. The flexibility of this funding mechanism also allows us to follow new directions of research as they emerge, ”says Chen.

Until relatively recently, it was thought that proteins needed to adopt a well-defined structure in order to perform their biological function. But about two decades ago, Chen explains, IDPs were recognized as a new class of proteins that rely on a lack of stable structures to function. They make up about one-third of the proteins the human body produces, Chen explains, and two-thirds of cancer-related proteins contain large, disordered segments or domains.

“This disorder seems to provide some unique functional advantage and that’s why we have so many disorders in certain types of proteins,” Chen says. “These IDPs play a very important role in biology, and when something goes wrong, they lead to very serious diseases, such as cancer and neurodegenerative diseases.”

In their lab, Chen and colleagues focus on using computer simulations to model the molecular structure and dynamics of proteins. “IDPs are a mess; it is difficult to determine the details of their properties because they are not subject to traditional techniques designed to resolve stable protein structures, ”he says.

Because of their chaotic state, IDPs must be described using ensembles of structures, and computer simulations play a key role in the quantitative description of these disordered entities. “Our goal is really to try to combine simulation and experiments in collaboration with other laboratories to discover what are the hidden features of these disrupted proteins that are crucial to their function,” Chen says. “Then we can look at how these specific features can be disrupted by mutations or disease-related conditions.”

The next step would be to develop effective strategies for targeting disrupted protein states. To that end, Chen’s lab will study the molecular basis of both the anti-cancer drug EGCG, an antioxidant found in green tea extract, and its derivatives interacting with the p53 gene, a tumor suppressor and the most important protein involved in cancer.

It is crucial, he says, to know how to design drug molecules to bind well enough to IDPs to achieve a therapeutic effect. Traditional structure-based drug design strategies face significant challenges, Chen says, because IDPs do not contain stable pockets that can be “drugged”.

“We believe that targeting IDPs requires new strategies that explore the dynamic nature of IDP interactions,” says Chen. “If we can do that, it could really open up a whole class of drugs that were previously considered impossible.”


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