Charge regulation in metalloproteins: from electron transfer to self-assembly.

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With this award, the Chemistry of Life Processes Program in the Chemistry Division is funding Dr. Bryan Shaw from Baylor University to investigate how the net electrostatic charge of proteins, Z, is affected by biochemical processes such as electron transfer. Most naturally-occurring proteins have a net electrostatic charge at neutral pH, that is an imbalance in the number of positively- and negatively-charged chemical groups of the protein. This net charge may affect many chemical processes involving proteins, such as electron transfer or protein aggregation. However, the charge Z at physiological pH has been measured for very few proteins. The lack of accurate measurements of Z may obscure a rigorous understanding of basic biochemistry; the knowledge of Z may create opportunities to chemically manipulate electrostatic forces inside living cells. Dr. Shaw's research group is using one of the very few tools available to rapidly measure Z to study how the net charge of a proteins is affected by electron transfer, molecular crowding, and protein aggregation and is also designing small molecules that can affect the electrostatic properties of proteins inside living cells. Dr. Shaw develops "mouth models" to enable students who are blind to use their touch and taste to visualize the structure and charge of proteins (Patent No. 10,043,413 B2). The mouth models are bite-sized exact 3D replicas of known proteins made of edible material. Students sense the structure of the model by placing the model in their mouth instead of sensing the model with their fingers.This research project seeks to answer the following scientific questions: how and why do metalloproteins regulate net charge during single electron transfer? When two proteins approach one another in solution to form a stable or transient complex (or to crowd), does the net charge of each protein affect the other's net charge by the magnitude predicted by theory? Can the electric field of a highly-charged protein alter the activity of a metalloenzyme with which it interacts? These questions are being addressed by measuring the net charge Z of folded proteins under various conditions using "protein charge ladders" and capillary electrophoresis. The new knowledge is applied to the design and chemical synthesis of aryl ester molecules that can selectively amplify the net charge of proteins via lysine acylation. These "charge boosting" molecules are designed to make possible electrostatic control the self-assembly of proteins into amyloid-like fibrils. The results of this research will deepen our fundamental understanding of the electrostatic forces in biological chemistry and to test the possibility that these forces can be chemically manipulated inside living cells.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.