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Biology 2015, 4(2), 344-366; doi:10.3390/biology4020344

Enrichment of Druggable Conformations from Apo Protein Structures Using Cosolvent-Accelerated Molecular Dynamics

1
Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI 48109, USA
2
Department of Internal Medicine, Hematology and Oncology Division, University of Michigan, Ann Arbor, MI 48109, USA
*
Authors to whom correspondence should be addressed.
Academic Editor: Thorsten Berg
Received: 24 February 2015 / Revised: 27 March 2015 / Accepted: 11 April 2015 / Published: 21 April 2015
(This article belongs to the Special Issue Protein-Protein Interactions)
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Abstract

Here we describe the development of an improved workflow for utilizing experimental and simulated protein conformations in the structure-based design of inhibitors for anti-apoptotic Bcl-2 family proteins. Traditional structure-based approaches on similar targets are often constrained by the sparsity of available structures and difficulties in finding lead compounds that dock against flat, flexible protein-protein interaction surfaces. By employing computational docking of known small molecule inhibitors, we have demonstrated that structural ensembles derived from either accelerated MD (aMD) or MD in the presence of an organic cosolvent generally give better scores than those assessed from analogous conventional MD. Furthermore, conformations obtained from combined cosolvent aMD simulations started with the apo-Bcl-xL structure yielded better average and minimum docking scores for known binders than an ensemble of 72 experimental apo- and ligand-bound Bcl-xL structures. A detailed analysis of the simulated conformations indicates that the aMD effectively enhanced conformational sampling of the flexible helices flanking the main Bcl-xL binding groove, permitting the cosolvent acting as small ligands to penetrate more deeply into the binding pocket and shape ligand-bound conformations not evident in conventional simulations. We believe this approach could be useful for identifying inhibitors against other protein-protein interaction systems involving highly flexible binding sites, particularly for targets with less accumulated structural data. View Full-Text
Keywords: Bcl-2 proteins; protein–protein interactions; principal component analysis; hierarchical clustering; binding site hotspot mapping; Sitemap; Bcl-xL inhibitors; computational docking Bcl-2 proteins; protein–protein interactions; principal component analysis; hierarchical clustering; binding site hotspot mapping; Sitemap; Bcl-xL inhibitors; computational docking
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

Kalenkiewicz, A.; Grant, B.J.; Yang, C.-Y. Enrichment of Druggable Conformations from Apo Protein Structures Using Cosolvent-Accelerated Molecular Dynamics. Biology 2015, 4, 344-366.

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