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Bioinformatics 2005 21(Suppl 1):i292-i301; doi:10.1093/bioinformatics/bti1005
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© The Author 2005. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions{at}oupjournals.org

High-throughput inference of protein–protein interfaces from unassigned NMR data

Ramgopal R. Mettu 1, Ryan H. Lilien 1,4 and Bruce Randall Donald 1,2,3,*

1Department of Computer Science, 6211 Sudikoff Laboratory Hanover, NH 03755, USA
2Department of Chemistry, Dartmouth College Hanover, NH 03755, USA
3Department of Biological Sciences, Dartmouth College Hanover, NH 03755, USA
4Dartmouth Medical School Hanover, NH 03755-1404, USA

*To whom correspondence should be addressed.

Summary: We cast the problem of identifying protein–protein interfaces, using only unassigned NMR spectra, into a geometric clustering problem. Identifying protein–protein interfaces is critical to understanding inter- and intra-cellular communication, and NMR allows the study of protein interaction in solution. However it is often the case that NMR studies of a protein complex are very time-consuming, mainly due to the bottleneck in assigning the chemical shifts, even if the apo structures of the constituent proteins are known. We study whether it is possible, in a high-throughput manner, to identify the interface region of a protein complex using only unassigned chemical shifts and residual dipolar coupling (RDC) data.

We introduce a geometric optimization problem where we must cluster the cells in an arrangement on the boundary of a 3-manifold. The arrangement is induced by a spherical quadratic form, which in turn is parameterized by a SO(3)xR2. We show that this formalism derives directly from the physics of RDCs. We present an optimal algorithm for this problem that runs in O(n3log n) time for an n-residue protein. We then use this clustering algorithm as a subroutine in a practical algorithm for identifying the interface region of a protein complex from unassigned NMR data. We present the results of our algorithm on NMR data for seven proteins from five protein complexes, and show that our approach is useful for high-throughput applications in which we seek to rapidly identify the interface region of a protein complex.

Availability: Contact authors for source code.

Contact: brd{at}cs.dartmouth.edu

Received on January 15, 2005; accepted on March 27, 2005

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