Understanding various chemical reactions and transport phenomena from the molecular and electronic level; designing new synthetic pathways for radical forms of materials and medicines; characterizing and rationalizing the behavior of matter far away from equilibrium—these are just a few of the grand scientific and engineering challenges that the newest research group in the Beckman Institute aims to tackle.
By bringing together various research efforts across campus and leveraging outstanding resources at Illinois, such as the Computational Science and Engineering (CSE) program and the National Center for Supercomputing Applications (NCSA), the group plans to lead large-scale research efforts in the area of computational molecular science that would be beyond the capability of an individual research group.
The Computational Molecular Science (CMS) Group has been established within the Molecular and Electronic Nanostructures research theme at the Beckman. Yang Zhang, a professor of nuclear, plasma, and radiological engineering, is named the founding group leader.
Along with Zhang, the other nine faculty members of the group include Charles Schroeder and Charles Sing of the Department of Chemical and Biomolecular Engineering; Narayana Aluru, of the Department of Mechanical Science and Engineering; Paul Braun, Andrew Ferguson, and Kenneth Schweizer, of the Department of Materials Science and Engineering; and Martin Gruebele, So Hirata, Nancy Makri, of the Department of Chemistry.
“Our goal is to consolidate campus-wide expertise on computational molecular science to facilitate interdisciplinary research in several strategic areas at the Beckman Institute and Illinois, and eventually establish a world-leading thrust in the frontier of theory-driven computational molecular science,” Zhang said.
CMS is profoundly interdisciplinary. It embodies physics, which underpins the underlying fundamental principles; chemistry, which both explores higher-level emergent principles and creates novel synthetic routes of remarkable organic, inorganic, bio-molecular building blocks that can self-assemble to structures with unique properties; and molecular biology and medical science, which are imperative to improve our health and quality of life.
“This group is an intellectual powerhouse with ambitious aspirations to advance important problems in molecular design thinking. Their activities cut across a number of experimental projects in the institute and so, wisely, the new CMS group integrated key experimentalists into its faculty roster,” said Jeff Moore, director of the Beckman Institute.
“The unique aspect of the CMS group is the emphasis of statistical and quantum mechanical theories-driven method development and applications,” said Zhang. “Through these computations, our ambition is to significantly extend our understanding of the equilibrium and non-equilibrium properties of matter from the molecular and electronic level, along with the creation of simulation, visualization, and analysis software packages that would become the golden standards in the field of CMS.”
The research topics of the CMS group include first-principle and semi-empirical methods, large-scale molecular dynamics simulations, advanced rare event sampling techniques, intelligent coarse graining and dimensionality reduction, and big data analysis – all targeted to advance molecular science. The impact of the work is amplified through close collaborations with experimentalists, synthetic chemists, materials scientists, and engineers.
The CMS group will synergistically collaborate with other groups, such as the Theoretical and Computational Biophysics and the Autonomous Materials Systems groups, at Beckman Institute.
Searching a whole genome for one particular sequence is like trying to fish a specific piece from the box of a billion-piece puzzle. Using advanced imaging techniques, University of Illinois researchers have observed how one set of genome-editing proteins finds its specific targets, which could help them design better gene therapies to treat disease.
Illinois chemical and biomolecular engineering professors Charles Schroeder and Huimin Zhao, along with graduate students Luke Cuculis and Zhanar Abil, published their work in the journal Nature Communications.
TALE proteins, or transcription activator-like effectors, can be programmed to recognize and bind to specific regions of DNA. Researchers have been interested in using TALE proteins for synthetic biology, such as genome editing in plants or bacteria, or for gene therapy. For example, Zhao’s group explores using TALE proteins to treat sickle cell anemia, which is caused by a mutation in one link of the DNA chain.
“People have been using this technique, but nobody fully understood the mechanism before,” Schroeder said. “The main question is, how do these proteins find their target sites? They are designed to bind to a particular site, but there’s this big genome with billions of bases, so how does the protein find its site? If you understand the mechanism, you might be able to engineer better, more improved proteins.”
The researchers used imaging techniques that let them watch through a microscope how individual TALE proteins interact with a string of DNA. They observed that the proteins seek and find using a combination of sliding and hopping. The proteins bind to the DNA and slide along the helix, traveling down the DNA molecule like a highway. The researchers also observed that the proteins perform frequent, short hops along their paths, allowing them to move more efficiently but never straying far from the DNA.
“The combination of sliding and hopping means they can cover more ground and potentially move past obstacles that might be in their way,” said Cuculis, a co-first author of the paper.
“The combination of behaviors also would allow a TALE protein to switch strands of the DNA double helix and sample both strands, increasing the chance of finding its target site,” said Abil, the other co-first author.
They also analyzed which parts of the protein did the work, finding a division of labor among the domains within the protein: One part searches, while another part binds to the specific target sequence. This finding excited the researchers, because it gave them insight into where to tweak the protein design so that it binds even more selectively.
“The major goal would be to engineer improved proteins that have lower off-target binding. You don’t want them to bind to the wrong place,” Schroeder said. “If we engineer a protein in such a way where we don’t just naively change the specific binding domain, but design a new protein with distinct parts of the protein in different places, we might be able to increase the efficiency without increasing mistakes.”
Next, the researchers are watching the proteins work in live cells to see if the behavior changes when immersed in the bustling activity within the cell nucleus.
“It gives us a better understanding of the genome editing mechanism,” Zhao said. “When we understand it better, it provides new insights for the design of the protein. If you really talk about therapeutic applications, it needs to be a specific design.”
The Carl R. Woese Institute for Genomic Biology at the U. of I. and the David and Lucile Packard Foundation supported this work. Schroeder and Zhao also are affiliated with the department of chemistry, the Center for Biophysics and Quantitative Biology, and the Carl R. Woese Institute for Genomic Biology at the U. of I.
–Liz Ahlberg, University of Illinois News Bureau