Rohit Pappu, the Edwin H. Murty Professor of Engineering at the McKelvey School of Engineering at Washington University in St. Louis, is part of multi-institution team to receive a highly competitive 2020 Multidisciplinary University Research Initiative (MURI) award from the Department of Defense.
The five-year $7.5 million grant is shared with three other universities and is aimed at uncovering the fundamental design principles that will enable researchers to design and engineer novel, synthetic and membraneless organelles.
This research will lead to the ability to control biochemical pathways and synthesize high-value compounds in yeast cells.
In addition to Pappu, the team includes Clifford Brangwynne and Jose Avalos from Princeton University; Ashutosh Chilkoti and Lingchong You from Duke University; and Amy Gladfelter from the University of North Carolina.
Certain stimuli can cause proteins to condense into membraneless organelles — squishy, liquid-like droplets that have defined phase boundaries but no delimiting membrane. Membraneless organelles arise from phase transitions in protein and RNA mixtures, and many of the proteins that drive these transitions encompass intrinsically disordered regions (IDR) of the protein. These are stretches of the protein with no defined, three-dimensional shape, and yet they feature prominently as molecular drivers and controllers of phase transitions.
The MURI team brings together experts, led by Brangwynne from Princeton, who made pioneering discoveries regarding the connections between phase transitions and the formation as well as the regulation of membraneless organelles. These organelles, referred to as biomolecular condensates, ensure that complex biochemical reactions underlying most cellular processes occur in the right place at the right time.
Over the past few years, Pappu and other members of the MURI group have worked together and separately to uncover some of the key principles that connect information written into protein and RNA sequences to the driving forces that give rise to condensates.
However, scientists still don’t fully comprehend what makes each condensate unique, thereby ensuring that each condensate performs specific sets of biochemical reactions. The MURI team has proposed that the surface features of condensates are the main determinants of selective permeability and the distinct functionalities of condensates. The plan is to bring novel methodologies to bear on the problem of describing condensate surfaces, connect these surface features to the information encoded in protein/RNA sequences, and design novel condensates with customizable surface features. These novel condensates are to be incorporated into yeast cells, which are hardy and can become novel active materials that function as microbial factories for a range of applications that are of interest to the U.S. Department of Defense.
Pappu, director of the Center for Science and Engineering of Living Systems at Washington University, and his team bring their fundamental knowledge of the physics of phase transitions and their ability to model protein and RNA specific phase behavior using a multifaceted, multi-physics computational pipeline.
He has introduced the so-called stickers-and-spacers framework, which reduces complex biological sequences to units that drive cohesive interactions (stickers) and units that regulate the driving forces for phase transitions (spacers). This framework has been instantiated into a series of computational engines that model phase behavior at different resolutions.