help button home button Biophys. J.
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH
Biophys. J. BioFAST: First Published May 4, 2007. doi:10.1529/biophysj.107.106146
© 2007 by the Biophysical Society.

A more recent version of this article appeared on September 1, 2007.
This Article
Right arrow Full Text (Rapid PDF)
Right arrow All Versions of this Article:
biophysj.107.106146v1
93/5/1474    most recent
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Pineda, J.R. E. T.
Right arrow Articles by Schwartz, S. D.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Pineda, J.R. E. T.
Right arrow Articles by Schwartz, S. D.

BIOPHYSICAL THEORY AND MODELING

Ligand Binding and Protein Dynamics in Lactate Dehydrogenase

J.R. Exequiel T. Pineda 1, Robert Callender 1 and Steven D. Schwartz 1*

1 Albert Einstein College of Medicine

* To whom correspondence should be addressed. E-mail: sschwartz{at}aecom.yu.edu.

Submitted on February 8, 2007
Revised on March 30, 2007
Accepted on 16 April 2007


  Abstract
Recent experimental studies suggest that lactate dehydrogenase binds its substrate via the formation of a LDH/NADH - substrate encounter complex through a 'select-fit' mechanism, whereby only a minority population of LDH/NADH is binding competent. In this study, we perform molecular dynamics calculations to explore the variations in structure accessible to the binary complex with a focus on identifying structures that seem likely to be binding competent and which are in accord with the know experimental characterization of forming binding competent species. We find that LDH/NADH samples quite a range of protein conformations within our 2.148 ns calculations, some of which yield quite facile access of solvent to the active site. The results suggest that the 'mobile loop' of LDH is perhaps just partially open in these conformations and that multiple open conformations, yielding multiple binding pathways, are likely. These ‘open’ conformations do not require large scale unfolding/melting of the binary complex. Rather, open versus closed conformations are due to subtle protein and water rearrangements. Nevertheless, the large heat capacity change observed between binding competent and binding incompetent can be explained by changes in solvation and an internal rearrangement of hydrogen bonds. We speculate that such a strategy for binding may be necessary to get a ligand efficiently to a binding pocket that is located fairly deep within the protein's interior.

Key Words: enzyme kinetics, ligand binding, protein conformations




This article has been cited by other articles:


Home page
 Biophys. JHome page
N. Zhadin, M. Gulotta, and R. Callender
Probing the Role of Dynamics in Hydride Transfer Catalyzed by Lactate Dehydrogenase
Biophys. J., August 15, 2008; 95(4): 1974 - 1984.
[Abstract] [Full Text] [PDF]

Home page
 Biophys. JHome page
H. Deng, S. Brewer, D. M. Vu, K. Clinch, R. Callender, and R. B. Dyer
On the Pathway of Forming Enzymatically Productive Ligand-Protein Complexes in Lactate Dehydrogenase
Biophys. J., July 15, 2008; 95(2): 804 - 813.
[Abstract] [Full Text] [PDF]

Home page
 Biophys. JHome page
L. Qiu, M. Gulotta, and R. Callender
Lactate Dehydrogenase Undergoes a Substantial Structural Change to Bind its Substrate
Biophys. J., September 1, 2007; 93(5): 1677 - 1686.
[Abstract] [Full Text] [PDF]


HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH
Copyright © 2007 by the Biophysical Society.