Structural Assembly of Molecular Complexes Based on Residual Dipolar Couplings

Abstract

We present and evaluate a rigid-body molecular docking method, called PATIDOCK, that relies solely on the three-dimensional structure of the individual components and the experimentally derived residual dipolar couplings (RDC) for the complex. We show that, given an accurate ab initio predictor of the alignment tensor from a protein structure, it is possible to accurately assemble a protein-protein complex by utilizing the RDC's sensitivity to molecular shape to guide the docking. The proposed docking method is robust against experimental errors in the RDCs and computationally efficient. We analyze the accuracy and efficiency of this method using experimental or synthetic RDC data for several proteins, as well as synthetic data for a large variety of protein-protein complexes. We also test our method on two protein systems for which the structure of the complex and steric-alignment data are available (Lys48-linked diubiquitin and a complex of ubiquitin and a ubiquitin-associated domain) and analyze the effect of flexible unstructured tails on the outcome of docking. The results demonstrate that it is fundamentally possible to assemble a protein-protein complex based solely on experimental RDC data and the prediction of the alignment tensor from three-dimensional structures. Thus, despite the purely angular nature of residual dipolar couplings, they can be converted into intermolecular distance/ translational constraints. Additionally we show a method for combining RDCs with other experimental data, such as ambiguous constraints from interface mapping, to further improve structure characterization of the protein complexes.

Recovering a Representative Conformational Ensemble from Underdetermined Macromolecular Structural Data

“…The ab initio prediction inadvertently introduces additional errors in our model. As we showed earlier 49 , in the case of steric alignment media for a two-domain system, these errors result in less than 4 Å RMSD between the actual and RDC-predicted structures. In other words, while the ab initio prediction might not be fully accurate in terms of the RDC fit, in terms of structural RMSD it is still relatively accurate, especially if we are interested in recovering large-scale motions between two domains, rather than small fluctuations.…”

Linkage via K27 Bestows Ubiquitin Chains with Unique Properties among Polyubiquitins

“…For each Ub, red, blue, and yellow sticks represent x, y, and z axes, respectively, of the alignment (A) or diffusion (B) tensor of Ub 2 (Table S1). The structures were determined using PATIDOCK (Berlin et al, 2010) (A) or ELMDOCK (Berlin et al, 2011) (B). Two structures are shown for each (differing by 180° rotation of the proximal Ub) due to orientational degeneracy of RDCs and relaxation rates (Fushman et al, 2004).…”

“… e Structures labeled ‘angle-optimized’ were generated using ELMDOCK (Berlin et al, 2011) (for 15 N relaxation data) or PATIDOCK (Berlin et al, 2010) (for RDC data) to obtain the best agreement between the experimental and predicted relaxation or RDC data for both Ubs taken together. …”

FANTEN: a new web-based interface for the analysis of magnetic anisotropy-induced NMR data

“…In this case the relevant tensor is the alignment tensor of the molecule, which depends both on the biomolecule and on the alignment medium. Command-line software packages (PALES and PATI) are available to fit RDCs arising from external alignment media and to give an estimate of the alignment tensor due to either steric effects or electrostatic effects or both (Zweckstetter and Bax 2000;Zweckstetter 2008;Berlin et al 2009Berlin et al , 2010Berlin et al , 2011.…”