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Title: Correlated structural kinetics and retarded solvent dynamics at the metalloprotease active site

Abstract

Solvent dynamics can play a major role in enzyme activity, but obtaining an accurate, quantitative picture of solvent activity during catalysis is quite challenging. Here, we combine terahertz spectroscopy and X-ray absorption analyses to measure changes in the coupled water-protein motions during peptide hydrolysis by a zinc-dependent human metalloprotease. These changes were tightly correlated with rearrangements at the active site during the formation of productive enzyme-substrate intermediates and were different from those in an enzyme–inhibitor complex. Molecular dynamics simulations showed a steep gradient of fast-to-slow coupled protein-water motions around the protein, active site and substrate. Our results show that water retardation occurs before formation of the functional Michaelis complex. We propose that the observed gradient of coupled protein-water motions may assist enzyme-substrate interactions through water-polarizing mechanisms that are remotely mediated by the catalytic metal ion and the enzyme active site.

Authors:
; ; ; ; ; ;
Publication Date:
Research Org.:
Brookhaven National Lab. (BNL), Upton, NY (United States)
Sponsoring Org.:
USDOE Office of Science (SC)
OSTI Identifier:
1069833
Report Number(s):
BNL-100405-2013-JA
Journal ID: ISSN 1545-9993
DOE Contract Number:  
AC02-98CH10886
Resource Type:
Journal Article
Journal Name:
Nature Structural & Molecular Biology
Additional Journal Information:
Journal Volume: 18; Journal Issue: 10; Journal ID: ISSN 1545-9993
Publisher:
Nature Publishing Group
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES

Citation Formats

Grossman, Moran, Born, Benjamin, Heyden, Matthias, Tworowski, Dmitry, Fields, Gregg B., Sagi, Irit, and Havenith, Martina. Correlated structural kinetics and retarded solvent dynamics at the metalloprotease active site. United States: N. p., 2011. Web. doi:10.1038/nsmb.2120.
Grossman, Moran, Born, Benjamin, Heyden, Matthias, Tworowski, Dmitry, Fields, Gregg B., Sagi, Irit, & Havenith, Martina. Correlated structural kinetics and retarded solvent dynamics at the metalloprotease active site. United States. doi:10.1038/nsmb.2120.
Grossman, Moran, Born, Benjamin, Heyden, Matthias, Tworowski, Dmitry, Fields, Gregg B., Sagi, Irit, and Havenith, Martina. Sun . "Correlated structural kinetics and retarded solvent dynamics at the metalloprotease active site". United States. doi:10.1038/nsmb.2120.
@article{osti_1069833,
title = {Correlated structural kinetics and retarded solvent dynamics at the metalloprotease active site},
author = {Grossman, Moran and Born, Benjamin and Heyden, Matthias and Tworowski, Dmitry and Fields, Gregg B. and Sagi, Irit and Havenith, Martina},
abstractNote = {Solvent dynamics can play a major role in enzyme activity, but obtaining an accurate, quantitative picture of solvent activity during catalysis is quite challenging. Here, we combine terahertz spectroscopy and X-ray absorption analyses to measure changes in the coupled water-protein motions during peptide hydrolysis by a zinc-dependent human metalloprotease. These changes were tightly correlated with rearrangements at the active site during the formation of productive enzyme-substrate intermediates and were different from those in an enzyme–inhibitor complex. Molecular dynamics simulations showed a steep gradient of fast-to-slow coupled protein-water motions around the protein, active site and substrate. Our results show that water retardation occurs before formation of the functional Michaelis complex. We propose that the observed gradient of coupled protein-water motions may assist enzyme-substrate interactions through water-polarizing mechanisms that are remotely mediated by the catalytic metal ion and the enzyme active site.},
doi = {10.1038/nsmb.2120},
journal = {Nature Structural & Molecular Biology},
issn = {1545-9993},
number = 10,
volume = 18,
place = {United States},
year = {2011},
month = {9}
}