Building quaternary structure in heme proteins

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Proteins are essential biological molecules that function as individual entities (protein monomers) or assemblies (dimers, trimers, tetramers, etc.). The ability of a protein monomer to become a part of a higher-order assembly is essential to biology, but to date, we still have only a limited understanding of how complex protein assemblies have evolved from simple monomers. A well-known protein is human hemoglobin, a tetramer which is precisely tuned for oxygen transport. With this award, the Chemistry of Life Processes Program in Chemistry is funding Dr. Juliette Lecomte of Johns Hopkins University to explore the modifications necessary to transform monomeric hemoglobins into dimeric assemblies endowed with new chemical properties. The hemoglobins that will be at the focus of the study are from unicellular organisms and artificial proteins with enhanced thermal resistance. The research applies a combined computational and experimental approach to the study of the hemoglobins. The university-level students who conduct the research become versed in the use of biophysical methods. An additional effort is directed to the integration of the results of the research into undergraduate courses in biochemistry and biophysical chemistry. High-school students from Baltimore City and surrounding areas are engaged by Dr. Lecomte and her students in scientific investigation during outreach activities.Truncated hemoglobins (TrHbs) are small proteins endowed with enzymatic activity related to the processing of reactive oxygen and nitrogen species. Some TrHbs adopt or sample a multimeric state in aqueous solution, suggesting a transition to an assembly with cooperative ligand binding properties. The focus of the research is the analysis and design of such multimeric states. Starting points are natural sequences from the piezophile Shewanella benthica and the green alga Chlamydomonas reinhardtii, and artificial hyperstable sequences derived from multiple sequence alignments. Electronic absorption and nuclear magnetic resonance spectroscopies are used to inspect nascent dimeric properties and the consequences of subunit association for ligand binding. The study provides fundamental information on the evolution of multimeric proteins and the control of their thermodynamic properties.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.