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 IDPs and therapeutic electric fields to externally modulate physiological and pathological protein behaviors through functionalization of their disordered behaviors. The use of disordered biochemical agents or disorder-inducing electric fields represents a novel approach to modulate protein (dys)function and to develop intervening therapeutics that target the disordered interactome. My goals are to bridge basic biophysical research in disordered protein folding to clinical departments that have not taken advantage of the immense impact of disordered therapeutics. Theoretical biophysical techniques, such as molecular dynamics (MD) simulations, are optimally suited for studying IDPs since they are capable of differentiating thermodynamic signatures of disorder that drive chemical functioning. When used in conjunction with experimental measurements such as NMR or CD, MD can help reinterpret protein data in the context of thermodynamic landscapes in order to inform how biology utilizes disorder. Prior attempts to do so have been limited by agents that interconverted globular proteins into alternate globular configurations. However, recent discoveries directly link disordered proteomes to novel biological functions such as protein phase separation, encapsulation, and soluble oligomerization, highlighting a vast number of emerging behaviors that can be conscripted for modern therapeutics or materials.