Fluitt hails from Lincoln, Nebraska. In 2010 he graduated from the University of Nebraska–Lincoln with a BS in chemical engineering. During his undergraduate studies, he worked in the research group of Professor Hendrik Viljoen and contributed to projects on protein synthesis rates, rapid polymerase chain reaction, and tuberculosis epidemiology and diagnostics. He then attended the University of Wisconsin–Madison on an NSF Graduate Research Fellowship and joined the research group of Professor Juan de Pablo, earning an MS in chemical engineering in 2013. He is now a PhD candidate in molecular engineering at the University of Chicago.
Approximately 350 million people worldwide are afflicted by diseases that share a common molecular origin: the misfolding and aggregation of a disease-specific protein. These include Alzheimer’s disease, type 2 diabetes, Parkinson’s disease, Huntington’s disease, Creutzfeldt-Jakob disease, amyotrophic lateral sclerosis (ALS), and others. The affected proteins have a wide range of native structures and functions, but all adopt a similar conformation known as amyloid in the context of mature aggregates. The observation of a common aggregate structure for otherwise dissimilar proteins suggests the existence of general principles governing protein misfolding and aggregation. An improved understanding of the molecular-scale thermodynamics and kinetics of these processes has the potential to guide the development of new therapies that target the formation of toxic aggregates.
Peptides containing an expanded polyglutamine (polyQ) repeat are a useful model system for protein aggregation, both for their own relevance in Huntington’s disease and for their intriguing aggregation properties. In particular, the appearance and severity of disease symptoms, as well as the rate of aggregation in vitro, depend on the length of the polyQ repeat. As in the other amyloid diseases, small aggregates of polyQ, or oligomers, are especially toxic to the cell, but characterizing their structure and mechanism of toxicity has been hampered by their small size and transient nature. Advanced molecular simulations and nonlinear spectroscopies possess the combination of structural and temporal resolution necessary to study structural dynamics during the early stages of aggregation of polyQ-containing peptides.
Using molecular dynamics simulations and specialized algorithms for sampling high-energy states and transition paths, Aaron studies the physical properties of polyQ-containing peptides in solution and in small aggregates. He is especially interested in identifying the thermodynamically stable and metastable conformations; identifying the misfolding and aggregation pathway(s), associated transition state(s), and rate constants; and evaluating their dependence on polyQ repeat length, primary sequence context, and the presence of inhibitors. Aaron collaborates actively with experimentalists and theorists who specialize in two-dimensional infrared spectroscopy, a powerful technique that provides extensive information on secondary structure, solvation, and dynamics. The combined expertise in simulation, theory, and experiment yields more detailed structural constraints than are possible with any one of these elements alone.
Guo, Ashley Z., Aaron M. Fluitt, and Juan J. de Pablo. "Early-stage human islet amyloid polypeptide aggregation: Mechanisms behind dimer formation." The Journal of chemical physics 149.2 (2018): 025101.
Membrane permeation versus amyloidogenicity: a multitechnique study of islet amyloid polypeptide interaction with model membranes
Martel, Anne, et al. "Membrane permeation versus amyloidogenicity: a multitechnique study of islet amyloid polypeptide interaction with model membranes." Journal of the American Chemical Society 139.1 (2016): 137-148.
Whitmer, Jonathan K., et al. "Sculpting bespoke mountains: Determining free energies with basis expansions." The Journal of chemical physics 143.4 (2015): 044101.
Fluitt, Aaron M., and Juan J. de Pablo. "An analysis of biomolecular force fields for simulations of polyglutamine in solution." Biophysical journal 109.5 (2015): 1009-1018.
Structural motif of polyglutamine amyloid fibrils discerned with mixed-isotope infrared spectroscopy
Lauren E. Buchanan, Joshua K. Carr, Aaron M. Fluitt, Andrew J. Hoganson, Sean D. Moran, Juan J. de Pablo, James L. Skinner, and Martin T. Zanni. PolyQ 2D IR. PNAS. 2014. Vol. 111, Pg. 5796-5801.