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Trout Group Member
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Naresh Chennamsetty
Post-Doctoral Associate
Department
of Chemical Engineering
MIT
Room: E19-528
77 Massachusetts Ave.
Cambridge, MA 02139 USA
Phone:
(617) 253-6675
Fax: (617) 253-2272
E-mail: naresh@mit.edu
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EDUCATION
Ph.D. North Carolina State University, Raleigh, NC
Chemical and Biomolecular Engineering, 2006
Advisor: Prof. Keith E. Gubbins
B.Tech. Indian Institute of Technology, Madras, India
Chemical Engineering, 2000
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RESEARCH SUMMARY
Molecular Insights into the Aggregation of Therapeutic Proteins:
We
employ molecular simulation tools in close collaboration with
genetic engineering and biophysical experiments to understand the
mechanism behind protein
aggregation. Therapeutic proteins such as antibodies constitute
the most rapidly growing class
of pharmaceuticals for the treatment of numerous cancers, chronic
inflammatory diseases, and infectious diseases. These antibodies
are stored for long term under high concentration conditions as
required for administration. These antibodies are, however,
thermodynamically unstable under these conditions and degrade due to
aggregation. Aggregation decreases protein activity and raises
concerns about an immunological response. Using full antibody
atomistic molecular dynamics simulations, we identify the antibody
regions prone to aggregation by using a technology that we developed
called ‘spatial-aggregation-propensity (SAP)’. SAP
identifies the location and size of these aggregation prone regions,
and allows us to perform target mutations of those regions to engineer
antibodies for stability. We apply this method to therapeutic
antibodies and demonstrate the significantly enhanced stability of our
mutants compared to the wild type.
Figure
1. The spatial-aggregation-propensity (SAP) values mapped for an IgG1
antibody. High SAP regions (in red) indicate the regions prone to
aggregation.
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PUBLICATIONS
• 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). PDF
• 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). PDF
• V. Voynov, N. Chennamsetty, V. Kayser, B. Helk, and B. L. Trout, “Predictive tools for stabilization of therapeutic proteins”, mAbs, 1, 580 (2009). PDF
• 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). PDF
• 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). PDF
• 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). PDF
PATENTS
• N. Chennamsetty, S. Ewert, B. Helk, B. L. Trout, and P. Wechner, “Novel antibody molecules and nucleic acids binding to fungal stress protein HSP90”, Patent # WO2008132152-A1 (2008)
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