Predicting the binding mode of flexible polypeptides to proteins is an important task that falls outside the domain of applicability of most small molecule and protein−protein docking tools. Here, we test the small molecule flexible ligand docking program Glide on a set of 19 non-α-helical peptides and systematically improve pose prediction accuracy by enhancing Glide sampling for flexible polypeptides. In addition, scoring of the poses was improved by post-processing with physics-based implicit solvent MM- GBSA calculations. Using the best RMSD among the top 10 scoring poses as a metric, the success rate (RMSD ≤ 2.0 Å for the interface backbone atoms) increased from 21% with default Glide SP settings to 58% with the enhanced peptide sampling and scoring protocol in the case of redocking to the native protein structure. This approaches the accuracy of the recently developed Rosetta FlexPepDock method (63% success for these 19 peptides) while being over 100 times faster. Cross-docking was performed for a subset of cases where an unbound receptor structure was available, and in that case, 40% of peptides were docked successfully. We analyze the results and find that the optimized polypeptide protocol is most accurate for extended peptides of limited size and number of formal charges, defining a domain of applicability for this approach.
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Arquitectura, E. Y., Introducci, T. I., 赫晓霞, Iv, T., Teatinas, L. A. S., Conclusiones, T. V. I. I., … Waldenström, L. (2015). Case Study Research Design and Methods. Acta Universitatis Agriculturae et Silviculturae Mendelianae Brunensis (Vol. 53, pp. 1689–1699). Retrieved from http://publications.lib.chalmers.se/records/fulltext/245180/245180.pdf%0Ahttps://hdl.handle.net/20.500.12380/245180%0Ahttp://dx.doi.org/10.1016/j.jsames.2011.03.003%0Ahttps://doi.org/10.1016/j.gr.2017.08.001%0Ahttp://dx.doi.org/10.1016/j.precamres.2014.12
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