Two Brown Scientists Join National Collaboration to Explore Genetic Mutations

Tuesday, August 08, 2017
GoLocalProv News Team

Daniel Weinreich
Two Brown University scientists will join a national collaboration funded by the National Science Foundation to discover how DNA leads to people’s traits.

Brown Faculty members Daniel Weinreich and Brenda Rubenstein will take on a four-year project to investigate how mutations cause differences in the way the proteins encoded by genes fold and blind.

The team will use a $1.5 million share of a new $6 million, four-year grant from the National Science Foundation.

“The fulcrum for all the work is the premise — to be tested — that by considering simple rules of biophysics we can predict what a mutation will do to its protein,” said Weinreich.

The Project

The team will model and experimentally test how different mutations could affect each of six different proteins.

Weinreich is an expert on the genetics and biology of the enzyme TEM-1 beta-lactamase, which helps to make bacteria drug resistant. Some mutations, or combinations of them, can undermine that trait. In the case of TEM-1, for example, the ability to fold into its normal configuration is necessary for it to become active — and the ability to bind to antibiotics is necessary for it to hinder the drug’s efficacy. Weinreich will lead the experimental testing of the predictions of the physicists in the enzyme.

Rubenstein’s lab will perform some of that modeling, not only in TEM-1 beta-lactamase but also the respiratory syncytial virus (RSV) fusion protein.

Working with computer simulations, she’ll develop an understanding of exactly how mutations alter the chemical structures of different amino acids and can affect the folding and binding of proteins.

Ultimately the entire team will study TEM-1, RSV, HIV, dihydrofolate reductase, which is an important enzyme in malarial drug resistance, the lytic bacteriophage phiX174, and EgfA-PDF.

The group will predict and test single mutations and combinations in each, as they look to learn more generally how mutation affects proteins and how that affects an organism’s traits.

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