Small-molecule ligand docking into comparative models with Rosetta.

Combs SA, Deluca SL, Deluca SH, Lemmon GH, Nannemann DP, Nguyen ED, Willis JR, Sheehan JH, Meiler J
Nat Protoc. 2013 8 (7): 1277-98

PMID: 23744289 · PMCID: PMC5750396 · DOI:10.1038/nprot.2013.074

Structure-based drug design is frequently used to accelerate the development of small-molecule therapeutics. Although substantial progress has been made in X-ray crystallography and nuclear magnetic resonance (NMR) spectroscopy, the availability of high-resolution structures is limited owing to the frequent inability to crystallize or obtain sufficient NMR restraints for large or flexible proteins. Computational methods can be used to both predict unknown protein structures and model ligand interactions when experimental data are unavailable. This paper describes a comprehensive and detailed protocol using the Rosetta modeling suite to dock small-molecule ligands into comparative models. In the protocol presented here, we review the comparative modeling process, including sequence alignment, threading and loop building. Next, we cover docking a small-molecule ligand into the protein comparative model. In addition, we discuss criteria that can improve ligand docking into comparative models. Finally, and importantly, we present a strategy for assessing model quality. The entire protocol is presented on a single example selected solely for didactic purposes. The results are therefore not representative and do not replace benchmarks published elsewhere. We also provide an additional tutorial so that the user can gain hands-on experience in using Rosetta. The protocol should take 5-7 h, with additional time allocated for computer generation of models.

MeSH Terms (8)

Drug Design Ligands Models, Molecular Molecular Docking Simulation Protein Conformation Sequence Alignment Software User-Computer Interface

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