Elucidation of the conformational free energy landscape in H.pylori LuxS and its implications to catalysis

Bhattacharyya, Moitrayee; Vishveshwara, Saraswathi
January 2010
BMC Structural Biology;2010, Vol. 10, p27
Academic Journal
Background: One of the major challenges in understanding enzyme catalysis is to identify the different conformations and their populations at detailed molecular level in response to ligand binding/environment. A detail description of the ligand induced conformational changes provides meaningful insights into the mechanism of action of enzymes and thus its function. Results: In this study, we have explored the ligand induced conformational changes in H.pylori LuxS and the associated mechanistic features. LuxS, a dimeric protein, produces the precursor (4,5-dihydroxy-2,3-pentanedione) for autoinducer-2 production which is a signalling molecule for bacterial quorum sensing. We have performed molecular dynamics simulations on H.pylori LuxS in its various ligand bound forms and analyzed the simulation trajectories using various techniques including the structure network analysis, free energy evaluation and water dynamics at the active site. The results bring out the mechanistic details such as co-operativity and asymmetry between the two subunits, subtle changes in the conformation as a response to the binding of active and inactive forms of ligands and the population distribution of different conformations in equilibrium. These investigations have enabled us to probe the free energy landscape and identify the corresponding conformations in terms of network parameters. In addition, we have also elucidated the variations in the dynamics of water co-ordination to the Zn2+ ion in LuxS and its relation to the rigidity at the active sites. Conclusions: In this article, we provide details of a novel method for the identification of conformational changes in the different ligand bound states of the protein, evaluation of ligand-induced free energy changes and the biological relevance of our results in the context of LuxS structure-function. The methodology outlined here is highly generalized to illuminate the linkage between structure and function in any protein of known structure.


Related Articles

  • Structure-Based Predictive Models for Allosteric Hot Spots. Demerdash, Omar N. A.; Daily, Michael D.; Mitchell, Julie C. // PLoS Computational Biology;Sep2009, Vol. 5 Issue 9, p1 

    In allostery, a binding event at one site in a protein modulates the behavior of a distant site. Identifying residues that relay the signal between sites remains a challenge. We have developed predictive models using support-vector machines, a widely used machine-learning method. The training...

  • Crystal Structure, SAXS and Kinetic Mechanism of Hyperthermophilic ADP-Dependent Glucokinase from Thermococcus litoralis Reveal a Conserved Mechanism for Catalysis. Rivas-Pardo, Jaime Andrés; Herrera-Morande, Alejandra; Castro-Fernandez, Victor; Fernandez, Francisco J.; Vega, M. Cristina; Guixé, Victoria // PLoS ONE;Jun2013, Vol. 8 Issue 6, p1 

    ADP-dependent glucokinases represent a unique family of kinases that belong to the ribokinase superfamily, being present mainly in hyperthermophilic archaea. For these enzymes there is no agreement about the magnitude of the structural transitions associated with ligand binding and whether they...

  • Structure-based design of a pathway-specific nuclear import inhibitor. Cansizoglu, Ahmet E.; Lee, Brittany J.; Zi Chao Zhang; Fontoura, Beatriz M. A.; Yuh Min Chook // Nature Structural & Molecular Biology;May2007, Vol. 14 Issue 5, p452 

    Kapβ2 (also called transportin) recognizes PY nuclear localization signal (NLS), a new class of NLS with a R/H/Kx(2–5)PY motif. Here we show that Kapβ2 complexes containing hydrophobic and basic PY-NLSs, as classified by the composition of an additional N-terminal motif, converge in...

  • CLIPS-1D: analysis of multiple sequence alignments to deduce for residue-positions a role in catalysis, ligand-binding, or protein structure.  // BMC Bioinformatics;2012, Vol. 13 Issue 1, p55 

    The article presents a study which aims at designing a new classifier which can differentiate between functionally and structurally important sites and to assess its performance on representative datasets. As mentioned, study was conducted by using CLIPS-1D classifier which predicts a role in...

  • Binding Pocket Optimization by Computational Protein Design. Malisi, Christoph; Schumann, Marcel; Toussaint, Nora C.; Kageyama, Jorge; Kohlbacher, Oliver; Höcker, Birte // PLoS ONE;Dec2012, Vol. 7 Issue 12, p1 

    Engineering specific interactions between proteins and small molecules is extremely useful for biological studies, as these interactions are essential for molecular recognition. Furthermore, many biotechnological applications are made possible by such an engineering approach, ranging from...

  • Structure-Based Virtual Screening. De Azevedo Jr., Walter Filgueira // Current Drug Targets;Mar2010, Vol. 11 Issue 3, p261 

    An introduction to the issue is presented, giving particular focus on development of structure-based virtual screening (SBVS) methodologies, including articles on modern computational approaches to molecular docking, evaluation of ligand binding affinity, and protein design.

  • Classification of Nonenzymatic Homologues of Protein Kinases. Anamika, K.; Abhinandan, K. R.; Deshmukh, K.; Srinivasan, N. // Comparative & Functional Genomics;2009, Special section p1 

    Protein Kinase-Like Non-kinases (PKLNKs), which are closely related to protein kinases, lack the crucial catalytic aspartate in the catalytic loop, and hence cannot function as protein kinase, have been analysed. Using various sensitive sequence analysis methods, we have recognized 82 PKLNKs...

  • Conformational Transitions upon Ligand Binding: Holo-Structure Prediction from Apo Conformations. Seeliger, Daniel; de Groot, Bert L. // PLoS Computational Biology;Jan2010, Vol. 6 Issue 1, p1 

    Biological function of proteins is frequently associated with the formation of complexes with small-molecule ligands. Experimental structure determination of such complexes at atomic resolution, however, can be time-consuming and costly. Computational methods for structure prediction of...

  • Computational chemistry: Designing optimal ligand-binding proteins. Harrison, Charlotte // Nature Reviews Drug Discovery;Oct2013, Vol. 12 Issue 10, p742 

    The article discusses research which designs ligand-binding proteins through in silico method, which references the article "Computational design of ligand-binding proteins with high affinity and selectivity," by C. E. Tinberg and colleagues in the 2013 issue.


Read the Article


Sorry, but this item is not currently available from your library.

Try another library?
Sign out of this library

Other Topics