Closing the side-chain gap in protein loop modeling |
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Authors: | Karen A Rossi Akbar Nayeem Carolyn A Weigelt Stanley R Krystek Jr |
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Institution: | (1) Bristol-Myers Squibb Company, Research & Development, Computer-Assisted Drug Design, P.O. Box 5400, Princeton, NJ 08543, USA |
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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.
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users. |
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Keywords: | Homology modeling Side-chain sampling Structure-based drug design |
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