skip to main content
OSTI.GOV title logo U.S. Department of Energy
Office of Scientific and Technical Information

Title: Intrinsic Motions Along an Enzymatic Reaction Trajectory

Abstract

The mechanisms by which enzymes achieve extraordinary rate acceleration and specificity have long been of key interest in biochemistry. It is generally recognized that substrate binding coupled to conformational changes of the substrate-enzyme complex aligns the reactive groups in an optimal environment for efficient chemistry. Although chemical mechanisms have been elucidated for many enzymes, the question of how enzymes achieve the catalytically competent state has only recently become approachable by experiment and computation. Here we show crystallographic evidence for conformational substates along the trajectory towards the catalytically competent 'closed' state in the ligand-free form of the enzyme adenylate kinase. Molecular dynamics simulations indicate that these partially closed conformations are sampled in nanoseconds, whereas nuclear magnetic resonance and single-molecule fluorescence resonance energy transfer reveal rare sampling of a fully closed conformation occurring on the microsecond-to-millisecond timescale. Thus, the larger-scale motions in substrate-free adenylate kinase are not random, but preferentially follow the pathways that create the configuration capable of proficient chemistry. Such preferred directionality, encoded in the fold, may contribute to catalysis in many enzymes.

Authors:
; ; ; ; ; ; ; ; ;
Publication Date:
Research Org.:
Brookhaven National Laboratory (BNL) National Synchrotron Light Source
Sponsoring Org.:
Doe - Office Of Science
OSTI Identifier:
959505
Report Number(s):
BNL-82491-2009-JA
TRN: US201016%%649
DOE Contract Number:
DE-AC02-98CH10886
Resource Type:
Journal Article
Resource Relation:
Journal Name: Nature; Journal Volume: 450
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; 99 GENERAL AND MISCELLANEOUS//MATHEMATICS, COMPUTING, AND INFORMATION SCIENCE; ACCELERATION; BIOCHEMISTRY; CATALYSIS; CHEMISTRY; CONFIGURATION; CONFORMATIONAL CHANGES; ENERGY TRANSFER; ENZYMES; FLUORESCENCE; NUCLEAR MAGNETIC RESONANCE; PHOSPHOTRANSFERASES; RESONANCE; SAMPLING; SPECIFICITY; SUBSTRATES; national synchrotron light source

Citation Formats

Henzler-Wildman,K., Thai, V., Lei, M., Ott, M., Wolf-Watz, M., Fenn, T., Pozharski, E., Wilson, M., Petsko, G., and et al. Intrinsic Motions Along an Enzymatic Reaction Trajectory. United States: N. p., 2007. Web. doi:10.1038/nature06410.
Henzler-Wildman,K., Thai, V., Lei, M., Ott, M., Wolf-Watz, M., Fenn, T., Pozharski, E., Wilson, M., Petsko, G., & et al. Intrinsic Motions Along an Enzymatic Reaction Trajectory. United States. doi:10.1038/nature06410.
Henzler-Wildman,K., Thai, V., Lei, M., Ott, M., Wolf-Watz, M., Fenn, T., Pozharski, E., Wilson, M., Petsko, G., and et al. Mon . "Intrinsic Motions Along an Enzymatic Reaction Trajectory". United States. doi:10.1038/nature06410.
@article{osti_959505,
title = {Intrinsic Motions Along an Enzymatic Reaction Trajectory},
author = {Henzler-Wildman,K. and Thai, V. and Lei, M. and Ott, M. and Wolf-Watz, M. and Fenn, T. and Pozharski, E. and Wilson, M. and Petsko, G. and et al},
abstractNote = {The mechanisms by which enzymes achieve extraordinary rate acceleration and specificity have long been of key interest in biochemistry. It is generally recognized that substrate binding coupled to conformational changes of the substrate-enzyme complex aligns the reactive groups in an optimal environment for efficient chemistry. Although chemical mechanisms have been elucidated for many enzymes, the question of how enzymes achieve the catalytically competent state has only recently become approachable by experiment and computation. Here we show crystallographic evidence for conformational substates along the trajectory towards the catalytically competent 'closed' state in the ligand-free form of the enzyme adenylate kinase. Molecular dynamics simulations indicate that these partially closed conformations are sampled in nanoseconds, whereas nuclear magnetic resonance and single-molecule fluorescence resonance energy transfer reveal rare sampling of a fully closed conformation occurring on the microsecond-to-millisecond timescale. Thus, the larger-scale motions in substrate-free adenylate kinase are not random, but preferentially follow the pathways that create the configuration capable of proficient chemistry. Such preferred directionality, encoded in the fold, may contribute to catalysis in many enzymes.},
doi = {10.1038/nature06410},
journal = {Nature},
number = ,
volume = 450,
place = {United States},
year = {Mon Jan 01 00:00:00 EST 2007},
month = {Mon Jan 01 00:00:00 EST 2007}
}