(2in) Theory and Design of Non-Natural Peptides That Undergo Folding-Induced Self-Assembly to Liquid-Liquid Phase Separation.

Naturally occurring peptide domains and proteins are a diverse category of biomacromolecules that continue to be widely explored due to their important role in cellular processes, widespread use in therapeutic formulations as well as their structural robustness and biocompatibility.¹ Some important avenues of exploration include investigation of protein folding and misfolding,² protein solution stability³ and peptide and protein bioconjugation with traditional polymers and their supramolecular self-assembly.^1,4–6 While notable advances have been made in these individual fields of research, much ground remains to be covered at the intersection between these fields. For example, the protein folding community is dominated by investigation of protein crystals and bioinformatics that seek to understand the static 3D folded structure of a naturally occurring protein. This has resulted in misinformation that the protein folding problem has been solved by the new neural network-based structure-prediction model of the AlphaFold software.⁷ However, it has been noted that the protein data bank is skewed towards sequence-to-structure relationships in crystallizable proteins, while a majority of proteins remain elusive. Such proteins usually have intrinsically disordered protein domains that are dynamic and often prone to misfolding.^8,9 Another significant blind spot in this field is the difficulty to predict protein-protein interactions that are crucial for predicting ligand-enzyme binding events and also for controlling stability of therapeutic formulations.¹⁰ Lastly, on the engineering front, scalable biomaterial construction using proteins and peptides continues to be a daunting task for engineers due to the complexity of the biomacromolecules, with most efforts focused of using naturally occurring biopolymers like silk fibroin, chitosan and collagen.^11,12

During my undergraduate studies in chemical engineering with a focus on polymer technology, I utilized silk fibroin to construct a novel scaffold for bone regeneration applications which resulted in an international patent as well as a commercial product that is currently under the clinical trials stage. As part of my Ph.D. thesis project, I utilized a new hybrid self-assembly pathway to construct supramolecular polymers of coiled coil-forming peptides, wherein the sequences were computationally designed using theory of protein folding. Our collaboration with computational design groups put me in a unique position to systematically investigate the solution behavior and assembly of a library of coiled coil-forming peptides with varying sequences and net charges, thus enabling elucidation of elusive structure-property relationships in naturally-occurring biomolecules. While pursuing my postdoctoral work, I have discovered an unprecedented phase behavior of oppositely charged homochiral peptide mixtures. This discovery has the potential of impacting our fundamental understanding of misfolding of intrinsically disordered proteins that results in various neurodegenerative diseases like Alzheimer’s disease. Concurrently, I am also spearheading an effort to design and synthesize a tunable and scalable biomaterial platform that utilizes peptide assemblies for 3d printing applications. Finally, my expertise in transmission electron microscopy and small-angle scattering characterization has benefitted multiple projects and graduate students across engineering and science disciplines at UC Santa Barbara.

Research Interests

My research program will address aforementioned scientific problems at the intersection of the fields of peptide and protein folding, interactions, and biomaterials construction. Combining the theory of polymer physics, biophysics and colloidal science with cutting-edge characterization techniques such as small-angle neutron and X-ray scattering, neutron spin echo and backscattering spectroscopy as well as cryo- and liquid-cell transmission electron microscopy, I will seek to answer fundamental questions in specifically designed peptide and proteins and subsequently utilize the created knowledge to build smart next-generation biomaterials. The synthesis tools that my group will employ will include solid-phase peptide synthesis (SPPS) to synthesize targeted peptide sequences, N-carboxyanhydride ring-opening polymerization (NCA-ROP) to construct polymeric and non-canonical peptides and finally, protein expression in Escherichia Coli to biosynthesize larger proteins.

Teaching Interests

My philosophy of effective pedagogy in the science and engineering fields has been informed by my own quest for knowledge and experiences as a student. After much deliberation and trial-and-error, my personal teaching philosophy can be reduced to following the steps of the three ‘I’s that I use every day to mentor undergraduate and graduate students. They are ‘Instill, Inspire, Innovate’. In my students I will instill a curiosity for scientific knowledge so they can independently identify a problem. Next, I will inspire them to pursue a scientifically sound solution to the identified problem. And finally, I will help them innovate a scientific solution to the identified problem.Within my own research group, I will seek to deliver as a teacher, mentor and guide to my future graduate students. I believe this to be the most important responsibility as faculty since the institution of academics is based on the forward dissemination of knowledge, skill and expertise. I will strive to foster a collaborative environment within my group as we pursue multidisciplinary research in the fields of chemical, biomaterial and biomedical sciences and engineering. I shall emphasize the importance of diversity, equity and inclusion, keeping channels of communications open to encourage cross-talk between disciplines will be crucial in inspiring and ushering the next generation of researchers.