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Link to original content: https://pubmed.ncbi.nlm.nih.gov/23579613
Effects of histidine protonation and rotameric states on virtual screening of M. tuberculosis RmlC - PubMed Skip to main page content
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. 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

Meekyum Olivia Kim  1 , Sara E Nichols, Yi Wang, J Andrew McCammon
Affiliations

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

Meekyum Olivia Kim et al. J Comput Aided Mol Des. 2013 Mar.

Abstract

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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Figures

Fig. 1
Fig. 1
Six possible protonation and rotameric states of a histidine. Formal charges on nitrogen in HIP states are marked
Fig. 2
Fig. 2
a RmlC homodimer in complex with co-crystalized 2′-deoxy-thymidine-β-l-rhamnose (TRH) (PDB ID: 2IXC). The two monomers are colored in pink and beige, respectively. b Close view of the co-crystal ligand TRH, with His62 and His119 highlighted. TRH is colored with carbon in violet, nitrogen in blue, oxygen in red, and phosphorus in orange. Protein residues are colored with carbon in salmon, while other atoms are following the same coloring scheme as TRH. The binding surface of receptor is represented as wire frame. Hydrogen bonds are shown with dashed green lines
Fig. 3
Fig. 3
Predicted interaction of the initial hit compound SID7975595 with flipped HID62 and HIP119 in receptor model 23. Generally, the actives do not have strong interactions with His62 or His119, yet varying histidine protonation states have a profound effect on the ranked results. Favorable interactions are observed with other binding site residues, such as Tyr132 and Tyr138 as depicted here
Fig. 4
Fig. 4
a AUC values of 36 receptor models. Protonation and rotameric states are marked for each histidine. Flipped states are marked with the letter F. Darker color indicates higher AUC and better predictive performance of the corresponding receptor model. b Average hydrogen bond percentage of the top 1 % compounds in 36 VS runs. Protonation and rotameric states are marked for each histidine. Lighter color indicates higher hydrogen bond percentage, with % unit for the colorbar. The R2 for the correlation between the AUCs and average hydrogen bond percentage for each VS run is 0.42 (see Online Resource 4 for the scatter plot). c Receptor performance dependence on His62 (top) and His119 (bottom). The median of the AUC values of each protonation state is shown with large horizontal line. The small ticks in each histidine model mark six different protonation states of the other histidine. The thicker vertical lines represent 25–75 % range of the AUCs. The best receptor models are shown explicitly with the models’ protonation states
Fig. 5
Fig. 5
a Interaction of the inactive compound 16952387 with flipped HID62 and HIE119 in receptor model 19. The compound has no interaction with either histidine. Pi–pi stacking interactions with Phe26 from chain B, Tyr132, and Tyr138 contribute to its high rank, along with hydrogen bonds with Arg23, Arg59, Arg170, and Ser51 (not shown). b Interaction of the inactive compound 17388064 with HIE62 and HID119 in receptor model 3. Both histidines provide hydrogen bonds to the compound
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