Zachary Levine, PhD

Functional, Pathological, and Engineered Protein Disorder

Structural and functional protein disorder is one of the most central, yet poorly understood drivers of human biology and disease. While a globular protein’s biophysical function is often derived from its three-dimensional structure, unstructured proteins carry out a diverse set of functions and can aggregate into physiological or pathological complexes, challenging the classical structure:function dogma. Despite their multifaceted ability to assist microtubule assembly, link protein domains, and seed the formation of amyloids in over twenty degenerative diseases, intrinsically disordered proteins (or IDPs) remain completely underutilized in molecular medicine, despite their occurrence in over 30% of the human proteome.

The goals of my research, broadly defined, are to leverage the immense power of the disordered proteome to modulate physiological and pathological protein behaviors in order to mitigate human diseases. The use of disordered peptides and biochemical compounds represents a novel approach to functionalize protein (dys)function, especially since multiple pathological protein targets interconvert between a number of transient states. My lab seeks to bridge predictive molecular models (MD simulations with enhanced-sampling) with in-vitro biophysics experiments of disordered proteins (NMR, ThT spectroscopy, chromatography, and immunoassays) in pathologically-inspired systems such as Alzheimer's disease and cancer, where water-soluble protein aggregates dictate disease severity.