title: Side-chain repacking calculations for predicting structures and stabilities of heterodimeric coiled coils.
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 A. 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.
authors.affiliation: Whitehead Institute for Biomedical Research, Howard Hughes Medical Institute, Department of Biology, Massachusetts Institute of Technology, Nine Cambridge Center, Cambridge, MA 02142, USA. keating@mit.edu
authors.forename: A E
authors.initials: AE
authors.lastname: Keating
authors.forename: V N
authors.initials: VN
authors.lastname: Malashkevich
authors.forename: B
authors.initials: B
authors.lastname: Tidor
authors.forename: P S
authors.initials: PS
authors.lastname: Kim
mesh_terms: D000595:Amino Acid Sequence; D002942:Circular Dichroism; D018360:Crystallography, X-Ray; D019281:Dimerization; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry; D011487:Protein Conformation
chemical_list: D010455:Peptides