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Side-Chain Repacking Calculations for Predicting Structures and Stabilities of Heterodimeric Coiled Coils

Amy E. Keating, Vladimir N. Malashkevich, Bruce Tidor and Peter S. Kim
Proceedings of the National Academy of Sciences of the United States of America
Vol. 98, No. 26 (Dec. 18, 2001), pp. 14825-14830
Stable URL: http://www.jstor.org/stable/3057370
Page Count: 6
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Abstract

An important goal in biology is to predict from sequence data the high-resolution structures of proteins and the interactions that occur between them. In this paper, we describe a computational approach that can make these types of predictions for a series of coiled-coil dimers. Our method comprises a dual strategy that augments extensive conformational sampling with molecular mechanics minimization. To test the performance of the method, we designed six heterodimeric coiled coils with a range of stabilities and solved x-ray crystal structures for three of them. The stabilities and structures predicted by the calculations agree very well with experimental data: the average error in unfolding free energies is <1 kcal/mol, and nonhydrogen atoms in the predicted structures superimpose onto the experimental structures with rms deviations <0.7 Å. We have also tested the method on a series of homodimers derived from vitellogenin-binding protein. The predicted relative stabilities of the homodimers show excellent agreement with previously published experimental measurements. A critical step in our procedure is to use energy minimization to relax side-chain geometries initially selected from a rotamer library. Our results show that computational methods can predict interaction specificities that are in good agreement with experimental data.

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