NDLI: Calculation of Vibrational Shifts of Nitrile Probes in the Active Site of Ketosteroid Isomerase upon Ligand Binding

Content Provider	PubMed Central
Author	Layfield, Joshua P. Sharon, Hammes-schiffer
Abstract	The vibrational Stark effect provides insight into the roles of hydrogen bonding, electrostatics, and conformational motions in enzyme catalysis. In a recent application of this approach to the enzyme ketosteroid isomerase (KSI), thiocyanate probes were introduced in site-specific positions throughout the active site. This paper implements a quantum mechanical/molecular mechanical (QM/MM) approach for calculating the vibrational shifts of nitrile (CN) probes in proteins. This methodology is shown to reproduce the experimentally measured vibrational shifts upon binding of the intermediate analog equilinen to KSI for two different nitrile probe positions. Analysis of the molecular dynamics simulations provides atomistic insight into the roles that key residues play in determining the electrostatic environment and hydrogen-bonding interactions experienced by the nitrile probe. For the M116C-CN probe, equilinen binding reorients an active site water molecule that is directly hydrogen bonded to the nitrile probe, resulting in a more linear CNH angle and increasing the CN frequency upon binding. For the F86C-CN probe, equilinen binding orients the Asp103 residue, decreasing the hydrogen-bonding distance between the Asp103 backbone and the nitrile probe and slightly increasing the CN frequency. This QM/MM methodology is applicable to a wide range of biological systems and has the potential to assist in the elucidation of the fundamental principles underlying enzyme catalysis.
Related Links	http://dx.doi.org/10.1021/ja3084384
Ending Page	725
Page Count	9
Starting Page	717
File Format	PDF
ISSN	00027863
e-ISSN	15205126
Journal	Journal of the American Chemical Society
Issue Number	2
Volume Number	135
Language	English
Publisher Date	2013-01-16
Access Restriction	Open
Subject Keyword	Colloid and Surface Chemistry Biochemistry Chemistry(all) Catalysis Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Chemistry Colloid and Surface Chemistry Biochemistry Catalysis

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