Integrative Structural Biology

Integrative Structural Biology

Integrative Structural Biology (#17)

Andrej Sali ¹

University of California at San Francisco, San Francisco, CA, United States

Andrej Sali. Department of Bioengineering and Therapeutic Science, Department of Pharmaceutical Chemistry, and California Institute for Quantitative Biosciences, Byers Hall, Suite 503B, 1700 4th Street, University of California, San Francisco, San Francisco, CA 94143-2330

The structures of macromolecular assemblies provide insights into their function and thus help us to understand the workings of living cells. Detailed structural characterization of large and often dynamic assemblies is generally impossible by any single existing experimental or computational method. This challenge can be overcome by hybrid approaches that integrate data from diverse biochemical and biophysical experiments (eg, X-ray crystallography, NMR spectroscopy, electron microscopy, chemical cross-linking, and small angle X-ray scattering).

We formulate the hybrid approach to structure determination as an optimization problem, the solution of which requires three main components: the representation of the assembly, the scoring function, and the optimization method. The ensemble of solutions to the optimization problem embodies the most accurate structural characterization given the available information. The key challenges remain translating experimental data into restraints on the structure of the assembly, combining these spatial restraints into a single scoring function, optimizing the scoring function, and analyzing the resulting ensemble of solutions.

To address these challenges, we are developing the open source Integrative Modeling Platform (IMP) (http://salilab.org/imp). IMP is designed to allow mixing and matching of existing modeling components as well as easy adding of new functionality. It supports a wide variety of assembly representations and input data. We also provide infrastructure that encourages and supports contributions from other laboratories.

The latest advances in our computational methods for integrative structure modeling will be outlined as well as illustrated by their application to the 26S proteasome and other systems.

D. Russel et al. Putting the pieces together: integrative structure determination of macromolecular assemblies. PLoS Biol 10, e1001244, 2012

Authors contributing to this presentation.

Sali, A

Andrej Sali received his BSc degree in chemistry from the University of Ljubljana, Slovenia, in 1987; and his PhD from Birkbeck College, University of London, UK, in 1991, under the supervision of Professor Tom L. Blundell, where he developed the MODELLER program for comparative modeling of protein structures. He was then a postdoc with Professor Martin Karplus at Harvard University as a Jane Coffin Childs Memorial Fund fellow, studying lattice Monte Carlo models of protein folding. From 1995 to 2002, he was first an Assistant Professor and then an Associate Professor at The Rockefeller University. In 2003, he moved to University of California, San Francisco, as a Professor of Computational Biology in the Department of Bioengineering and Therapeutic Sciences, Department of Pharmaceutical Chemistry, and California Institute for Quantitative Biosciences (QB3). He was a Sinsheimer Scholar (1996), an Alfred P. Sloan Research Fellow (1998), an Irma T. Hirschl Trust Career Scientist (2000), and the recipient of the Zois Award of Science Ambassador of Republic of Slovenia (2007). He is an Editor of Structure and a Founder of Prospect Genomix that merged with Structural Genomix, finally acquired by E. Lilly & Co. Dr. Sali is interested in developing and applying computational methods for determining structures and functions of proteins and their assemblies.

Integrative Structural Biology (#17)

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