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Electronic properties of the transition state for RhoA-catalyzed phosphoryl transfer revealed by F NMR and computational analysis

Project Leads: PI: Dr. Nigel Richards (Department of Chemistry & Chemical Biology, Indiana University Purdue University Indianapolis, Indianapolis, IN 46202, USA) Lead: Dr. Robert Molt Jr. (Department of Chemistry & Chemical Biology, Indiana University Purdue University Indianapolis, Indianapolis, IN 46202, USA) and Dr. Yi Jin (Krebs Institute, Molecular Biology and Biotechnology, University of Sheffield, Sheffield, S10 2TN, UK) Associated Scientists: Dr. George M. Blackburn (Krebs Institute, Molecular Biology and Biotechnology, University of Sheffield, Sheffield, S10 2TN, UK) and Dr. Jon Waltho (Krebs Institute, Molecular Biology and Biotechnology, University of Sheffield, Sheffield, S10 2TN, UK and Manchester Institute of Biotechnology, Manchester, M1 7DN, UK)

Research made possible by:  High Performance Systems (HPS), Scientific Applications and Performance Tuning (SciAPT); Big Red II supercomputer

The nucleophilic attack of water on the metaphosphate (gamma phosphorus of GTP); we can see the GDP as the leaving group. A complex network of hydrogen bonds has been established guiding the key functionality, as well as potent targets to destabilize the transition state if desired.
Figure 1. The nucleophilic attack of water on the metaphosphate (gamma phosphorus of GTP); we can see the GDP as the leaving group. A complex network of hydrogen bonds has been established guiding the key functionality, as well as potent targets to destabilize the transition state if desired.
Cancer is ultimately the lack of an off-switch for certain chemical reactions. In healthy cells, the off-switch operates normally, and cells know when to stop copying themselves to make new cells. In cancers, something goes wrong with the proper functionality of this on/off switch such that it stays permanently in the "on" mode. We have provided the chemical play-by-play of how this switch works in healthy cells. This knowledge of exactly what atoms go where allows biochemists to design inhibitors to stop cancer, since now they know how healthy cells are supposed to work.

The Big Red 2 Supercomputer has been critical to the success of 6 projects in researching cancer, developing new tools for protein study, designing better explosives for the U.S. Army, creating stable artificial DNA to augment existing human DNA, new equations to describe the quantum mechanics of molecular electronics, and new models of bonding in organic chemistry.

Our research has proven the validity of an inorganic molecule as a transition state mimic, allowing biochemists everywhere to use it to study any protein/enzyme they wish to study. We used this inorganic molecule to study a protein critical to the deadliest types of cancers. Our work illustrates the molecular structure of the proteins in healthy, non-cancerous cells that regulate cell growth biochemically. This same protein molecular structure is defective in cancerous cells; we now have a point of reference for what must go wrong in cancerous cells.

The mission of the Scientific Applications and Performance Tuning (SciAPT) group is to deliver and support software tools that promote effective and efficient use of IU's advanced cyberinfrastructure which, in turn, improves research and enables discoveries.

The High Performance Systems (HPS) group implements, operates, and supports some of the fastest supercomputers in the world. IU's Big Red II, the Quarry cluster, Karst, and the large memory Mason system in order to advance Indiana University's mission in research, training, and engagement in the state. HPS also supports databases and database engines used by the IU community.

NSF GSS Codes:

Primary Field: Physiology (615) Oncology and Cancer Biology

Secondary Fields:  Chemistry (202) Organic Chemistry and Preventive Medicine and Community Health