Electrostatic fields near the active site of human aldose reductase: 1. New inhibitors and vibrational stark effect measurements

Biochemistry
Lauren J Webb, Steven G Boxer

Abstract

Vibrational Stark effect spectroscopy was used to measure electrostatic fields in the hydrophobic region of the active site of human aldose reductase (hALR2). A new hALR2 inhibitor was designed and synthesized that contains a nitrile probe with a Stark tuning rate of 0.77 cm-1/(MV/cm). Mutations to amino acid residues in the vicinity of the nitrile functional group were selected based on electrostatics calculations, possible complications from hydrogen bonds near the nitrile, and comparison with the active site of human aldehyde reductase, whose structure is very similar. Changes in the absorption energy of the nitrile probe when bound to those mutated proteins were then used to quantify perturbations to the protein's electrostatic field. Electrostatic field changes as large as -10 MV/cm were observed. Measured electrostatic fields were compared to predictions based on continuum electrostatics calculations, revealing that substantial modifications to the calculation strategy are necessary. The effects of hydrogen bonding of amino acid side chains to the nitrile probe are considered, and applications of vibrational Stark effect spectroscopy to investigations of ligand binding and biological function are discussed.

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Citations

May 18, 2013·Chemical Reviews·Heejae Kim, Minhaeng Cho
Jun 15, 2012·Journal of the American Chemical Society·Sayan BagchiSteven G Boxer
Oct 16, 2013·Journal of the American Chemical Society·Predrag KukicJens Erik Nielsen
Oct 5, 2010·The Journal of Physical Chemistry. B·Aaron T Fafarman, Steven G Boxer
Dec 1, 2011·The Journal of Physical Chemistry. B·Samrat DuttaChristopher M Cheatum
Mar 28, 2012·The Journal of Physical Chemistry. B·Nicholas M LevinsonSteven G Boxer
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Sep 17, 2009·Physical Chemistry Chemical Physics : PCCP·Beth A LindquistSteven A Corcelli
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