(5n) Elucidating Protein Binding and Aggregation

My overall research goal is to understand the mechanisms behind protein binding and aggregation using multi-scale modeling and simulation techniques in close collaboration with experiments.  Protein binding is vital to its function in a variety of biological processes such as cellular communication, metabolism, gene expression, and immune responses. On the other hand, aggregation disrupts protein function and is associated with a number of neurodegenerative disorders such as Alzheimer's and Creutzfeldt-Jakob diseases, and type II diabetes.  Furthermore, aggregation of proteins in therapeutic formulations leads to loss of their activity and raises concerns of potential immunogenicity.  My research is aimed at understanding the mechanisms behind these protein binding and aggregation processes, and to design proteins with improved binding and stability.

I.  Mechanisms for Binding and Aggregation of Therapeutic Proteins

In my current post-doctoral position with Prof. Bernhardt L. Trout at the Massachusetts Institute of Technology, we study the mechanism behind binding and aggregation of therapeutic antibodies and we design antibodies with enhanced stability.^1,2  Antibodies constitute the most rapidly growing class of human therapeutics for use in the treatment of numerous cancers, chronic inflammatory diseases, and infectious diseases. These antibodies are, however, thermodynamically unstable under conditions required for storage and administration and degrade due to aggregation.  We developed a molecular simulation tool called spatial-aggregation-propensity (SAP) in collaboration with experimental techniques to identify the regions of the antibody most prone to aggregation.  Subsequently, we perform mutations in these specific aggregation prone regions to engineer antibodies with enhanced stability.  We also developed methods for predicting protein-binding regions with good accuracy.

II. Development of Multi-scale Modeling and Simulation Techniques for Soft Condensed Matter Systems

During my PhD work with Prof. Keith E Gubbins at North Carolina State University, we developed a multi-scale methodology connecting the atomistic and meso-scale models useful in understanding surfactant self-assembly, polymers, colloids and protein solutions.³  We also developed a novel coarse-graining technique to determine rigorous effective potentials.⁴  In addition, we used meso-scale models to explore the effect of cosolvents and cosurfactants such as alcohols on surfactant self-assembly in supercritical carbon dioxide with applications in separation processes in the food industry such as extraction of water-soluble vitamins and proteins, dry cleaning and polymerization.⁵

References:

1.  N. Chennamsetty, V. Voynov, V. Kayser, B. Helk and B. L. Trout, "Design of therapeutic proteins with enhanced stability", Proc. Natl. Acad. Sci. U.S.A., 106, 11937 (2009). This also appears as research highlight, "Unstuck by design", in Nature, 460, 155 (2009)

2.  N. Chennamsetty, B. Helk, V. Voynov, V. Kayser, and B. L. Trout, "Aggregation Prone Motifs in Human Immunoglobulin G", J. Mol. Biol., 391, 404 (2009)

3.  J. R. Silbermann, S. H. L. Klapp, M. Schoen, N. Chennamsetty, H. Bock and K. E. Gubbins, "Mesoscale modeling of complex binary fluid mixtures: Towards an atomistic foundation of effective potentials", J. Chem. Phys., 124, 074105 (2006)

4.  N. Chennamsetty, H. Bock, K. E. Gubbins, "Coarse-grained potentials from Widom's particle insertion method", Special issue in honor of Ben Widom, Mol. Phys., 103, 3185 (2005)

5.  N. Chennamsetty, H. Bock, L. F. Scanu, F. R. Siperstein, and K. E. Gubbins, "Cosurfactant and cosolvent effects on surfactant self-assembly in supercritical carbon dioxide" J. Chem. Phys., 122, 94710 (2005)