Abstract
The success of structure-based drug design relies on accurate protein modeling where one of the key issues is the modeling and refinement of loops. This study takes a critical look at modeled loops, determining the effect of re-sampling side-chains after the loop conformation has been generated. The results are evaluated in terms of backbone and side-chain conformations with respect to the native loop. While models can contain loops with high quality backbone conformations, the side-chain orientations could be poor, and therefore unsuitable for ligand docking and structure-based design. In this study, we report on the ability to model loop side-chains accurately using a variety of commercially available algorithms that include rotamer libraries, systematic torsion scans and knowledge-based methods.
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Acknowledgments
We would like to thank the following people for helpful discussions as well as assistance with software: Hongwei Huang (Accelrys), Tamsin Mansley (Tripos), Andrew Orry (Molsoft), and Woody Sherman (Schrödinger).
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Rossi, K.A., Nayeem, A., Weigelt, C.A. et al. Closing the side-chain gap in protein loop modeling. J Comput Aided Mol Des 23, 411–418 (2009). https://doi.org/10.1007/s10822-009-9274-3
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DOI: https://doi.org/10.1007/s10822-009-9274-3