Research Areas in the Roberts Laboratory


The vast majority of biopharmaceutical products (as opposed to “small-molecule” drugs such as tablets and capsules) that are available commercially or are in late-stage clinical testing are based on one or more proteins as the active ingredient. Biopharmaceuticals are also the fastest-growing sector of the pharmaceutical industry, and target diseases ranging from diabetes and cancer to auto-immune disorders. Many of the research projects in the Roberts laboratory are motivated by or directly focused on topics that fall within the general topic of protein stability and assembly within the context of biotechnology projects.

Current Group Members: Lily Motobar, Terrance Shoemaker, James Forder, Jordan Berger, Hassan Shahfar, Veerabhadraiah Palakollu

Protein-protein and protein-solute interactions

Proteins interact continuously with the surrounding solvent, other proteins, and (co)solutes in solution. Those interactions span from strong “binding” events to weaker interactions. When considering weaker interactions, averaged over the entire ensemble of protein configurations and surrounding molecular environment, these tend to strongly influence protein phase behavior, separation processes, and protein aggregation rates. Research in this area focuses on improved experimental and theoretical ways to quantify the relevant interactions, as well as how these change as one moves across a broad range of solution conditions that are needed for manufacturing and application of biotechnology products. This work is supported by funding from the NSF, NIH, NIST and a number of biopharmaceutical companies.

Recent Publications:

Protein (mis)folding, aggregation, and phase behavior

Proteins are heteropolymers of amino acids that typically must be properly folded in order to perform their biological function or to be useful as biotechnology products. An ever growing body of experimental evidence shows that correct folding and function is in competition with “off pathway” protein-protein interactions that result in misfolded or non-native aggregates composed of multiple protein chains. Although the exact role of such aggregates in the progression of neurodegenerative diseases remains unclear, insoluble aggregates are clearly causative agents for diseases such as cataracts and amyloidoses. More important from the perspective of pharmaceutical products, soluble or insoluble aggregates are a major risk factor for unwanted patient immune responses and safety issues with some protein-based products.





Research in this area focuses on elucidating the key mechanistic stages for aggregation of a range of different proteins, so as to gain insights regarding how to change product formulation or manufacturing conditions to balance the different stages of aggregation when one is seeking to maximize shelf life and/or control the morphology and size of the resulting aggregates. This involves a variety of experimental methods, as well as kinetic and thermodynamic modeling. This work is supported by funding from the NIH, NIST, and a number of biopharmaceutical companies.

Recent Publications:

Protein interactions, aggregation, and viscosity at high concentrations

Protein interactions and stability can be dramatically altered by moving from traditional “low” protein-concentration conditions (< approx.. 10 g/L) to “high” concentrations (~ 150+ g/L). Working at high concentrations can alter unfolding free energies, increase viscosity to unmanageable levels, induce phase separation, and greatly accelerate aggregation. Research in our group focuses on development of improved experimental and theoretical methods to quantify and predict how protein interactions and the resulting product properties are altered by moving from low to high protein concentrations. This work is supported by funding from the NIH, NIST and a number of biopharmaceutical companies.

Recent Publications:

Modeling and design for folding and assembly of proteins, peptides, and hybrid materials

Folding and assembly of proteins requires a careful balance of a number of competing forces at the molecular level. Similarly, assembly of advanced nanostructured materials can take advantage of those competing forces. However, in both cases it is difficult to a priori predict what affects a change in the chemical structure of a protein or peptide-based material will have on the final structure and morphology of the new protein or material. Research in this area focuses on development and application of existing and new, improved models to predict how changes in variables such as peptide sequence will alter the conformational stability and aggregation of proteins, as well as the assembly of peptide-based hybrid materials.

Recent Publications:

Improved prediction of protein (in)stability

Proteins degrade in a variety of ways, and must remain viable (with minimal degradation) over multiple years in order to be commercially practical as drug products. However, early-stage development activities are typically based on small supplies of protein material, and require development decisions to be reached on time scales that are much shorter than those needed to directly monitor protein degradation in the laboratory. In addition, degradation can be accelerated unexpectedly once the protein is produced in commercial-scale facilities and/or is exposed to deviations from its recommended storage conditions. Historically, proteins have required refrigerated or even frozen storage in order to maintain sufficient shelf life. However, this neglects a large portion of the world’s population that do not have the infrastructure to maintain a “cold chain” for the lifetime of a protein product. Research in the group focuses on development of improved engineering-science approaches and physics-based models to predict key product attributes such as aggregate formation, phase separation, and rheological properties.

Recent Publications:

Protein adsorption at solid-liquid and air-liquid interfaces

Protein adsorption to bulk interfaces is often unavoidable, and can have significant impacts on protein stability in the context of the manufacture, storage, and administration of protein-based products. Efforts in this research area focus generally on understanding key factors that control the adsorption/desorption processes, the structural nature of adsorbed protein films, how these processes impact the formation of protein aggregates and visible/subvisible particles that are potentially detrimental in protein-based products, and how best to measure properties of the interface.

Recent Publications: