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Dr. Jeffrey Gray


Techniques for biomolecular modeling of protein assembly and function


Assistant Professor, Chemical and Biomolecular Engineering, Johns Hopkins Whiting School of Engineering


Ph.D., Chemical Engineering, University of Texas at Austin


Fellow, Biochemistry, University of Washington, Seattle

Research Summary

Dr. Gray develops techniques for biomolecular modeling of protein assembly and function, including protein-protein docking, allostery, and protein-surface interactions. Dr. Gray wrote the RosettaDock algorithm, which is a multiscale routine that can rapidly search docking conformational space and accurately identify near-native conformations. Current work is improving recognition for proteins with backbone flexibility and tailoring the algorithm for application to therapeutic antibodies, including those applicable in cancer studies. Functional application to allosteric proteins and bionanoengineering application to protein-surface interactions is are being developed.

Therapeutic antibodies provide relief from various human diseases and provide a strategy for several new and promising treatments for cancer. One such strategy targets the epidermal growth factor receptor (EGFR), since EGFR signaling is implicated in a wide variety of cancers (breast, ovarian, head and neck, lung, pancreatic, colorectal),. In particular, monoclonal antibody (mAb) 806 binds EGFR, but unlike similar anti-EGFR drugs, it binds cancer cells exclusively, thus avoiding side effects such as hair and skin loss. However, the mAb 806-EGFR structure is unknown, limiting both our understanding of the drug mechanism and our ability to rationally improve the drug. Our objectives are to predict the structure of the complex of mAb 806 bound to EGFR and to improve methodologies for docking of therapeutic antibodies in general such that predicted structures are of sufficient quality for rational drug design and engineering. We are appling RosettaDock, our multi-scale protein-protein docking algorithm, and we are combining it with novel homology modeling and free energy calculations to create accurate structural models. This research will enable rapid and inexpensive means to understand the molecular basis of new cancer therapeutics, and it will enable the rational design and improvement of mAb 806 and the entire class of antibody drugs.

In a new study relevant to cancer research, we are studying the molecular motions and underlying mechanisms of allosteric proteins. Allosteric proteins have two distinct biochemical states (e.g. active and inactive) dependent upon the presence of an effector molecule such as GTP or a hormone. Transcription factors, signaling proteins, and regulatory proteins are allosteric, and cancer cells often hijack these proteins to set them permanently in one particular state to enable cell proliferation. For example, the signaling protein /ras/ is permanently switched ‘on’ in 30 percent of all solid tumors. We have collected a large set of structures of allosteric proteins and we are mining this set to describe the structural mechanism of switching. We are also using network theory to determine the nature of the intramolecular signal transduction. Finally, we are using Rosetta to simulate the conformational transitions experienced by these proteins in response to a signal. These simulations and structural studies will help us to identify particular target sites for drug design to restore the normal functioning of these proteins. This work will ultimately speed rational design of small molecule cancer drugs.

For additional information on Dr. Gray's research, see http://graylab.jhu.edu


EM 5/06

Journal Citations

Berrondo, M.; Gray, J.J.; Schleif, R. Computational predictions of the mutant behavior of AraC. J Mol Biol. 2010 May 7;398(3):462-470.

Chaudhury, S.; Lyskov, S.; Gray, J.J. PyRosetta: a script-based interface for implementing molecular modeling algorithms using Rosetta. Bioinformatics. 2010 Mar 1;26(5):689-691.

Masica, D.L.; Ash, J.T.; Ndao, M.; Drobny, G.P.; Gray, J.J. Toward a structure determination method for biomineral-associated protein using combined solid- state NMR and computational structure prediction. Structure. 2010 Dec 8;18(12):1678-1687.

Sircar, A.; Chaudhury, S.; Kilambi, K.P.; Berrondo, M.; Gray, J.J. A generalized approach to sampling backbone conformations with RosettaDock for CAPRI rounds 13-19. Proteins. 2010 Nov 15;78(15):3115-3123.
Sircar, A.; Gray, J.J. SnugDock: paratope structural optimization during antibody-antigen docking compensates for errors in antibody homology models. PLoS Comput Biol. 2010 Jan;6(1):e1000644.

A. Sircar & J. J. Gray, "SnugDock: Paratope structural optimization during antibody-antigen docking compensates for errors in antibody homology models," PLoS Comput. Biol. 6(1): e1000644 (2010). Online | PDF

S. Chaudhury & J. J. Gray, "Identification of structural mechanisms of HIV-1 protease specificity using computational peptide docking and implications for drug resistance," Structure 17(12), 1636-1648 (2009). Online | PDF

Y.-C. Chien, D. L. Masica, J. J. Gray, S. Nguyen, H. Vali & M. D. McKee, "Modulation of calcium oxalate dehydrate growth by selective crystal-face binding of phosphorylated osteopontin and poly-aspartate peptide showing occlusion by sectoral (compositional) zoning," J. Biol. Chem. 284, 23491-23501 (2009). Online| PDF

W. N. Addison, D. L. Masica, J. J. Gray & M. D. McKee, "Phosphorylation-dependent inhibition of mineralization by osteopontin ASARM peptides is regulated by PHEX cleavage," J. Bone & Mineral Research, available in WebFirst (2009).

A. Sircar,* E. Kim* & J. J. Gray, "RosettaAntibody: Antibody Variable Region Homology Modeling Server," Nucleic Acids Research 37 (Web Server Issue), W474-W479 (2009).

M.D. Daily & J. J. Gray, "Allosteric communication occurs via networks of tertiary and quaternary motions in proteins," PLoS Comput. Biol. 5(2): e1000293 (2009).

A. Sivasubramanian,* A. Sircar,* S. Chaudhury & J. J. Gray, "Toward high-resolution homology modeling of antibody Fv regions and application to antibody-antigen docking," Proteins 74(2), 497-514 (2009). Online | PDF (*These authors contributed equally to this work)

S. Chaudhury & J. J. Gray, "Conformer selection and induced fit in flexible backbone protein-protein docking using computational and NMR ensembles," J. Mol. Biol. 381(4), 1068-1087 (2008).

S. Lyskov & J. J. Gray, "The RosettaDock server for local protein-protein docking," Nucleic Acids Research 36 (Web Server Issue), W233-W238 (2008).

S. Chaudhury,* A. Sircar,* A. Sivasubramanian, M. Berrondo & J. J. Gray, "Incorporating biochemical information and backbone flexibility in RosettaDock for CAPRI rounds 6-12," Proteins 69(4), 793-800 (2007). Online | PDF (*These authors contributed equally to this work.)

A. Sivasubramanian, J. A. Maynard, & J. J. Gray, "Modeling the structure of mAb 14B7 bound to the anthrax protective antigen," Proteins 70(1), 218-230 (2008).

A. Sivasubramanian, G. Chao, H.M. Pressler, K.D. Witrup, and J.J. Gray, "Structural model of the mAb 806-EGFR complex using computational docking followed by computational and experimental mutagenesis," Structure 14(3), 401-414 (2006).

Singh, A.M. Mhaka, S.B. Christensen, J.J. Gray, S.R. Denmeade, and J.T. Isaacs, "Applying linear interaction energy method for rational design of non-competitive allosteric inhibitors of the SERCA ATPase," J. Med. Chem. 48(8), 3005-3014 (2005).


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