Aalt van Dijk

HADDOCK versus HADDOCK: New features and performance of HADDOCK2.0 on the CAPRI targets

Here we present version 2.0 of HADDOCK, which incorporates considerable improvements and new features. HADDOCK is now able to model not only protein–protein complexes but also other kinds of biomolecular complexes and multi‐component (N > 2) systems. In the absence of any experimental and/or predicted information to drive the docking, HADDOCK now offers two additional ab initio docking modes based on either random patch definition or center‐of‐mass restraints. The docking protocol has been considerably improved, supporting among other solvated docking, automatic definition of semi‐flexible regions, and inclusion of a desolvation energy term in the scoring scheme. The performance of HADDOCK2.0 is evaluated on the targets of rounds 4‐11, run in a semi‐automated mode using the original information we used in our CAPRI submissions. This enables a direct assessment of the progress made since the previous versions. Although HADDOCK performed very well in CAPRI (65% and 71% success rates, overall and for unbound targets only, respectively), a substantial improvement was achieved with HADDOCK2.0. Proteins 2007.

Data-driven docking for the study of biomolecular complexes

With the amount of genetic information available, a lot of attention has focused on systems biology, in particular biomolecular interactions. Considering the huge number of such interactions, and their often weak and transient nature, conventional experimental methods such as X‐ray crystallography and NMR spectroscopy are not sufficient to gain structural insight into these. A wealth of biochemical and/or biophysical data can, however, readily be obtained for biomolecular complexes. Combining these data with docking (the process of modeling the 3D structure of a complex from its known constituents) should provide valuable structural information and complement the classical structural methods. In this review we discuss and illustrate the various sources of data that can be used to map interactions and their combination with docking methods to generate structural models of the complexes. Finally a perspective on the future of this kind of approach is given.

WHISCY: What Information Does Surface Conservation Yield? Application to Data-Driven Docking

Protein–protein interactions play a key role in biological processes. Identifying the interacting residues is a first step toward understanding these interactions at a structural level. In this study, the interface prediction program WHISCY is presented. It combines surface conservation and structural information to predict protein–protein interfaces. The accuracy of the predictions is more than three times higher than a random prediction. These predictions have been combined with another interface prediction program, ProMate [Neuvirth et al. J Mol Biol 2004;338:181–199 ], resulting in an even more accurate predictor. The usefulness of the predictions was tested using the data‐driven docking program HADDOCK [Dominguez et al. J Am Chem Soc 2003;125:1731–1737 ] in an unbound docking experiment, with the goal of generating as many near‐native structures as possible. Unrefined rigid body docking solutions within 10 Å ligand RMSD from the true structure were generated for 22 out of 25 docked complexes. For 18 complexes, more than 100 of the 8000 generated models were correct. Our results demonstrates the potential of using interface predictions to drive protein–protein docking. Proteins 2006.

Various strategies of using residual dipolar couplings in NMR-driven protein docking: Application to Lys48-linked di-ubiquitin and validation against 15N-relaxation data

When classical, Nuclear Overhauser Effect (NOE)‐based approaches fail, it is possible, given high‐resolution structures of the free molecules, to model the structure of a complex in solution based solely on chemical shift perturbation (CSP) data in combination with orientational restraints from residual dipolar couplings (RDCs) when available. RDCs can be incorporated into the docking following various strategies: as direct restraints and/or as intermolecular intervector projection angle restraints (Meiler et al., J Biomol NMR 2000;16:245–252). The advantage of the latter for docking is that they directly define the relative orientation of the molecules. A combined protocol in which RDCs are first introduced as intervector projection angle restraints and at a later stage as direct restraints is shown here to give the best performance. This approach, implemented in our information‐driven docking approach HADDOCK (Dominguez et al., J Am Chem Soc 2003;125:1731–1737), is used to determine the solution structure of the Lys48‐linked di‐ubiquitin, for which chemical shift mapping, RDCs, and 15N‐relaxation data have been previously obtained (Varadan et al., J Mol Biol 2002;324:637–647). The resulting structures, derived from CSP and RDC data, are cross‐validated using 15N‐relaxation data. The solution structure differs from the crystal structure by a 20° rotation of the two ubiquitin units relative to each other. Proteins 2005.

Dose escalation study of rhenium-186 hydroxyethylidene diphosphonate in patients with metastatic prostate cancer

Rhenium-186 hydroxyethylidene diphosphonate (186Re-HEDP) has been used for the palliative treatment of metastatic bone pain. A phase 1 dose escalation study was performed using 186Re-HEDP Twenty-four patients with hormone-resistant prostate cancer entered the study. Each patient had at least four bone metastases and adequate haematological function. Groups of at least three consecutive patients were treated with doses starting at 1295 MBq and increasing to 3515 MBq (escalated in increments of 555 MBq). Thrombocytopenia proved to be the dose-limiting toxicity, while leucopenia played a minor role. Early death occurred in one patient (10 days after administration) without clear relationship to the 186Re-HEDP therapy. Transient neurological dysfunction was seen in two cases. Two patients who received 3515 MBq 186Re-HEDP showed grade 3 toxicity (thrombocytes 25–50 × 109/1), defined as unacceptable toxicity. After treatment alkaline phosphatase levels showed a transient decrease in all patients (mean: 26% ± 10% IUA; range: 11%–44%). Prostate-specific antigen values showed a decline in eight patients, preceded by a temporary increase in three patients. From this study we conclude that the maximally tolerated dose of 186Re-HEDP is 2960 MBq. A placebo-controlled comparative study on the efficacy of 186Re-HEDP has been initiated.

Interferon-alpha induced changes in CEA expression in patients with CEA-producing tumours

Abstract.Enhancement of antigen expression could result in improved tumour targeting using antibodies directed to the antigen. In this study we performed radioimmunoscintigraphy using 99mTc-CEA-Scan to analyse the effect of interferon-alpha (IFN-α) in enhancing the expression of carcinoembryonic antigen (CEA) in ten patients with CEA-producing tumours. Furthermore, we investigated the feasibility of a future therapeutic study with this antibody fragment labelled with rhenium-186. Although IFN-α gave rise to a significant increase in antibody uptake by the tumour, the absolute antibody uptake in the tumour appeared to be poor, with a mean of 0.475% of injected dose (ID) in the tumour before IFN-α, rising to 0.562% ID in the tumour after IFN-α. Pharmacokinetic analysis demonstrated no significant alterations after IFN-α. In conclusion, the administration of IFN-α is an attractive way to achieve enhanced tumour targeting, although the increase was of little clinical significance in this patient population and using this antibody fragment.