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Results: 6

1.
Fig. 1

Fig. 1. From: Predicting ligand binding affinity with alchemical free energy methods in a polar model binding site.

A. T4 Lysozyme L99A/M102Q binding site shown in complex with phenol and one ordered water molecule 23. B. Unwinding of Helix-F upon binding of certain ligands (cyan) yields an enlarged binding site relative to apo (orange).

Sarah E. Boyce, et al. J Mol Biol. ;394(4):747-763.
2.
Fig. 6

Fig. 6. From: Predicting ligand binding affinity with alchemical free energy methods in a polar model binding site.

Crystallographic orientations of the reference ligands phenol (orange, PDB ID 1LI2) and catechol (cyan, PDB ID 1XEP) overlayed on the apo reference structure (gray, PDB ID 1LGU). The two alternate hydroxyl positions are labeled A & B.

Sarah E. Boyce, et al. J Mol Biol. ;394(4):747-763.
3.
Fig. 2

Fig. 2. From: Predicting ligand binding affinity with alchemical free energy methods in a polar model binding site.

Representative isothermal titration calorimetry measurements and fit: n-phenylglycinonitrile titration (stock concentration 1.4mM) into L99A/M102Q (initial concentration 42.5μM). An initial injection of 2μL was followed by 29 ×10μL injections of ligand to a final ligand concentration in the reaction cell of 237.9μM.

Sarah E. Boyce, et al. J Mol Biol. ;394(4):747-763.
4.
Fig. 5

Fig. 5. Relative binding free energy predictions from reference compounds Catechol & Phenol. From: Predicting ligand binding affinity with alchemical free energy methods in a polar model binding site.

The experimental free energy of binding was determined by ITC at 10°C for each compound; the relative binding free energy for each ligand to the experiment is shown in gray. The calculated relative free energy of binding relative to the reference compound catechol is shown in green and to phenol in magenta.

Sarah E. Boyce, et al. J Mol Biol. ;394(4):747-763.
5.
Fig 4

Fig 4. Comparison of predicted to experimental binding modes for the relative binding free energy predictions starting from reference compounds catechol & phenol. From: Predicting ligand binding affinity with alchemical free energy methods in a polar model binding site.

A. & B. Two conformations of 2-methoxyphenol: A. X-ray result, 50:50 occupancy. 2Fo−Fc electron density map displayed at 1.0σ. B. Overlay of x-ray result (gray), prediction from catechol (green & cyan), RMSD 0.52 and 0.85Å, and prediction from phenol (magenta), RMSD 0.65 Å. C. & D. 2-ethoxyphenol: C. X-ray result,100% occupancy. 2Fo−Fc electron density map displayed at 1.5σ. D. Overlay of x-ray result (gray) and prediction from catechol (green & cyan), RMSD 0.58 and 0.76Å, and prediction from phenol (magenta), RMSD 0.86Å. E. & F. Two conformations of 2-methylphenol: E. X-ray result, 50:50 occupancy. 2Fo−Fc electron density map displayed at 1.0σ. F. Overlay of x-ray result (gray) and prediction from catechol (green), RMSD 1.02Å, and prediction from phenol (magenta), RMSD 2.03Å. G. & H. 2-propylphenol: G. X-ray result,100% occupancy. 2Fo−Fc electron density map displayed at 1.5σ. H. Overlay of x-ray result (gray) and prediction from catechol (green & cyan), RMSD 0.40 and 1.08Å, and prediction from phenol (magenta), RMSD 2.23Å. I. & J. 2-ethylphenol: I. X-ray result, 100% occupancy. 2Fo−Fc electron density map displayed at 1.5σ. J. Overlay of x-ray result (gray) and prediction from catechol (green, cyan, yellow), RMSD 0.64Å, 3.10Å, 3.08Å and prediction from phenol (magenta), RMSD 2.25Å. K. & L. 5-chloro-2-methylphenol: K. X-ray result, 100% occupancy. 2Fo−Fc electron density map displayed at 1.5σ. L. Overlay of x-ray result (gray) and prediction from catechol (green), RMSD 0.87Å, and prediction from phenol (magenta), RMSD 0.66Å.

Sarah E. Boyce, et al. J Mol Biol. ;394(4):747-763.
6.
Fig. 3

Fig. 3. Comparison of predicted to experimental binding modes for the absolute binding free energy predictions. From: Predicting ligand binding affinity with alchemical free energy methods in a polar model binding site.

A. & B. Two conformations of benzylacetate: A. X-ray result, 25:25 occupancy. 2Fo−Fc electron density map displayed at 1.0σ. B. Overlay of x-ray result (gray) with predicted geometry (green). C. & D. Two conformations of thiophene-2-carboxaldoxime: A. X-ray result, 50:50 occupancy. 2Fo−Fc electron density map displayed at 1.5σ. B. Overlay of x-ray result (gray) with predicted geometry (green).E. & F. Two conformations of thieno[3,2-b]thiophene: A. X-ray result, 50:50 occupancy. 2Fo−Fc electron density map displayed at 1.5σ. B. Overlay of x-ray result (gray) with predicted geometries (green & cyan).G. & H. Two conformations of 2-nitrothiophene: A. X-ray result, 50:50 occupancy. 2Fo−Fc electron density map displayed at 1.5σ. B. Overlay of x-ray result (gray) with predicted geometries (green & cyan). I. & J. Two molecules of 4-chloro-1H-pyrazole: A. X-ray result, two molecules (A & B) bound at 100% occupancy with two ordered water molecules. 2Fo−Fc electron density map displayed at 1.5σ. B. Overlay of x-ray result (gray) with predicted geometry (green). K. & L. N-phenylglycinonitrile: A. X-ray result, 100% occupancy. 2Fo−Fc electron density map displayed at 1.5σ. B. Overlay of x-ray result (gray) with predicted geometry (green). M. & N. 4,5,6,7-tetrahydroindole: A. X-ray result, 50% occupancy. 2Fo−Fc electron density map displayed at 1.0σ. B. Overlay of x-ray result (gray) with predicted geometries (green & cyan). O. & P. Two conformations of nitrosobenzene: A. X-ray result, 25:25 occupancy. 2Fo−Fc electron density map displayed at 1.0σ. B. Overlay of x-ray result (gray) with predicted geometry (green). Q. & R. 2-ethoxy-3,4-dihydro-2h-pyran: A. X-ray result, 25% occupancy. 2Fo−Fc electron density map displayed at 0.5σ. B. Overlay of x-ray result (gray) with predicted geometry (green).

Sarah E. Boyce, et al. J Mol Biol. ;394(4):747-763.

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