A NMR-spectra-based scoring function for protein docking

A well studied problem in the area of Computational Molecular Biology is the so-called Protein-Protein Docking problem (PPD) that can be formulated as follows: Given two proteins A and B that form a protein complex, compute the 3D-structure of the protein complex AB. Protein docking algorithms can be used to study the driving forces and reaction mechanisms of docking processes. They are also able to speed up the lenghty process of experimental structure elucidation of protein complexes by proposing potential structures. In this paper, we are discussing a variant of the PPD-problem where the input consists of the tertiary structures of A and B plus an unassigned 1H-NMR spectrum of the complex AB. We present a new scoring function for evaluating and ranking potential complex structures produced by a docking algorithm. The scoring function computes a “theoretical” 1H-NMR spectrum for each tentative complex structure and subtracts the calculated spectrum from the experimental spectrum. The absolute areas of the difference spectra are then used to rank the potential complex structures. In contrast to formerly published approaches (e.g. Morelli et. al. [38]) we do not use distance constraints (intermolecular NOE constraints). We have tested the approach with the bound conformations of four protein complexes whose three-dimensional structures are stored in the PDB data bank [5] and whose 1H-NMR shift assignments are available from the BMRB database (BioMagResBank [47]). In all examples, the new scoring function produced very good rankings of the structures. The best result was obtained for an example, where all standard scoring functions failed completely. Here, our new scoring function achieved an almost perfect separation between good approximations of the true complex structure and false positives. Unfortunately, the number of complexes with known structure and available spectra is very small. Nevertheless, these experiments indicate that scoring functions based on comparisons of one- or multi-dimensional NMR spectra might be a good instrument to improve the reliability and accuracy of docking predictions and perhaps also of protein structure predictions (threading).