Boaz Shapira

Hydrophobic complementarity in protein–protein docking

Formation of hydrophobic contacts across a newly formed interface is energetically favorable. Based on this observation we developed a geometric–hydrophobic docking algorithm that estimates quantitatively the hydrophobic complementarity at protein–protein interfaces. Each molecule to be docked is represented as a grid of complex numbers, storing information regarding the shape of the molecule in the real part and information regarding the hydropathy of the surface in the imaginary part. The grid representations are correlated using fast Fourier transformations. The algorithm is used to compare the extent of hydrophobic complementarity in oligomers (represented by D2 tetramers) and in hetero‐dimers of soluble proteins (complexes). We also test the implication of hydrophobic complementarity in distinguishing correct from false docking solutions. We find that hydrophobic complementarity at the interface exists in oligomers and in complexes, and in both groups the extent of such complementarity depends on the size of the interface. Thus, the non‐polar portions of large interfaces are more often juxtaposed than non‐polar portions of small interfaces. Next we find that hydrophobic complementarity helps to point out correct docking solutions. In oligomers it significantly improves the ranks of nearly correct reassembled and modeled tetramers. Combining geometric, electrostatic and hydrophobic complementarity for complexes gives excellent results, ranking a nearly correct solution < 10 for 5 of 23 tested systems, < 100 for 8 systems and < 1000 for 19 systems. Proteins 2004.

Single‐Scan 2D Hadamard NMR Spectroscopy

Scan and deliver: By combining imaging-based spectral/spatial 2D radiofrequency manipulations (see scheme, left) with Hadamard-weighting principles, 2D NMR spectra can be retrieved within a single scan (right). This approach can give homo- or heteronuclear correlations with an enhanced sensitivity over conventional ultrafast 2D NMR spectroscopy.

Prediction of the unknown: Inspiring experience with the CAPRI experiment

We submitted predictions for all seven targets in the CAPRI experiment. For four targets, our submitted models included acceptable, medium accuracy predictions of the structures of the complexes, and for a fifth target we identified the location of the binding site of one of the molecules. We used a weighted‐geometric docking algorithm in which contacts involving specified parts of the surfaces of either one or both molecules were up‐weighted or down‐weighted. The weights were based on available structural and biochemical data or on sequence analyses. The weighted‐geometric docking proved very useful for five targets, improving the complementarity scores and the ranks of the nearly correct solutions, as well as their statistical significance. In addition, the weighted‐geometric docking promoted formation of clusters of similar solutions, which include more accurate predictions. Proteins 2003;52:41–46.

Electron-nuclear interactions as probes of domain motion in proteins

Long range interactions between nuclear spins and paramagnetic ions can serve as a sensitive monitor of internal motion of various parts of proteins, including functional loops and separate domains. In the case of interdomain motion, the interactions between the ion and NMR-observable nuclei are modulated in direction and magnitude mainly by a combination of overall and interdomain motions. The effects on observable parameters such as paramagnetic relaxation enhancement (PRE) and pseudocontact shift (PCS) can, in principle, be used to characterize motion. These parameters are frequently used for the purpose of structural refinements. However, their use to probe actual domain motions is less common and is lacking a proper theoretical treatment from a motional perspective. In this work, a suitable spin Hamiltonian is incorporated in a two body diffusion model to produce the time correlation function for the nuclear spin-paramagnetic ion interactions. Simulated observables for nuclei in different positions with respect to the paramagnetic ion are produced. Based on these simulations, it demonstrated that both the PRE and the PCS can be very sensitive probes of domain motion. Results for different nuclei within the protein sense different aspects of the motions. Some are more sensitive to the amplitude of the internal motion, others are more sensitive to overall diffusion rates, allowing separation of these contributions. Experimentally, the interaction strength can also be tuned by substitution of different paramagnetic ions or by varying magnetic field strength (in the case of lanthanides) to allow the use of more detailed diffusion models without reducing the reliability of data fitting.