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J Comput Aided Mol Des. 2013 Mar;27(3):235-46. doi: 10.1007/s10822-013-9643-9. Epub 2013 Apr 12.

Effects of histidine protonation and rotameric states on virtual screening of M. tuberculosis RmlC.

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Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, CA 92093, USA.


While it is well established that protonation and tautomeric states of ligands can significantly affect the results of virtual screening, such effects of ionizable residues of protein receptors are less well understood. In this study, we focus on histidine protonation and rotameric states and their impact on virtual screening of Mycobacterium tuberculosis enzyme RmlC. Depending on the net charge and the location of proton(s), a histidine can adopt three states: HIP (+1 charged, both δ- and ε-nitrogens protonated), HID (neutral, δ-nitrogen protonated), and HIE (neutral, ε-nitrogen protonated). Due to common ambiguities in X-ray crystal structures, a histidine may also be resolved as three additional states with its imidazole ring flipped. Here, we systematically investigate the predictive power of 36 receptor models with different protonation and rotameric states of two histidines in the RmlC active site by using results from a previous high-throughput screening. By measuring enrichment factors and area under the receiver operating characteristic curves, we show that virtual screening results vary depending on hydrogen bonding networks provided by the histidines, even in the cases where the ligand does not obviously interact with the side chain. Our results also suggest that, even with the help of widely used pKa prediction software, assigning histidine protonation and rotameric states for virtual screening can still be challenging and requires further examination and systematic characterization of the receptor-ligand complex.

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