Handling Protein Flexibility

Although such approaches lead to a significant speedup over methods that treat the protein as fully flexible, they are still too time consuming for screening purposes. Therefore, one is interested in introducing protein flexibility into the much faster, fragmentation-based approaches. 

The screening software SPECITOPE, developed by Schnecke et al.156, uses distance matrix comparisons as a first filter step. Elowever, flexibility of molecules is not modeled by distance intervals. Instead, a weighting scheme is defined to scale down the contributions of more flexible atom pairs in the overall score. In addition, a special optimizer is added that allows the removal of protein-ligand steric clashes after the placement calculation. 

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Protein flexibility as the second major challenge is discussed in two separate chapters. The first is dedicated primarily to the algorithmic description of the methods available for handling protein flexibility, based on a new classification of the different approaches. The second chapter focuses on their application in high-throughput docking and virtual screening. As these chapters illustrate, a multitude of different approaches are already available for at least partial consideration of protein... 

Handling Protein Flexibility in Docking and High-Throughput Docking From Algorithms to Applications... 

As this short example shows. PDB files use different syntax for different records and both writing and reading such files require much effort. Another problem is the extensibility of this format to handle new kinds of information, which further complicates the file structure. The Protein Data Bank has been faced with the consequences - the existing legacy data comply with several different PDB formats, so they are not uniform and they arc more difEcuh to handle (145, 155, 157]. As mentioned in Section 2,9.7.1, there is a much more flexible and general way of representing molecular structure codes and associated information - the STAR file format and the file formats based on it. 

Nevertheless, Quijada et al. [13] described a very sensitive application of the IPCR method, using protein-chimeras for the preimplantation detection of histocompatiblity. In this assay, single murine blastocystes as analytical targets were handled without immobilization to microplate surfaces, and therefore with no need for capture antibodies. The authors reported that the broad binding ability of protein A was turned to an advantage for the flexible detection of nonfunctionalized antibodies. Further application of the STV/protein A chimera in IPCR was described for a similar expression... 

The docking problem in its full generality is likely to remain an open problem even in the long term. Too many subproblems are still unsolved, the most urgent ones being the accurate prediction of binding affinity and the handling of protein conformational flexibility. 

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