Related ArticlesSearching For Protein Binding Sites From Molecular Dynamics Simulations and Paramagnetic Fragment-based NMR Studies.
Biochim Biophys Acta. 2013 Dec 26;
Authors: Bernini A, De Angelis LH, Morandi E, Spiga O, Santucci A, Assfalg M, Molinari H, Pillozzi S, Arcangeli A, Niccolai N
Abstract
Hotspot delineation on protein surfaces represents a fundamental step for targeting protein-protein interfaces. Disruptors of protein-protein interactions can be designed provided that the sterical features of binding pockets, including the transient ones, can be defined. Molecular Dynamics, MD, simulations have been used as a reliable framework for identifying transient pocket openings on the protein surface. Accessible surface area and intramolecular H-bond involvement of protein backbone amides are proposed as descriptors for characterizing binding pocket occurrence and evolution along MD trajectories. TEMPOL induced paramagnetic perturbations on (1)H-(15)N HSQC signals of protein backbone amides have been analyzed as a fragment-based search for surface hotspots, in order to validate MD predicted pockets. This procedure has been applied to CXCL12, a small chemokine responsible for tumor progression and proliferation. From combined analysis of MD data and paramagnetic profiles, two CXCL12 sites suitable for the binding of small molecules were identified. One of these sites is the already well characterized CXCL12 region involved in the binding to CXCR4 receptor. The other one is a transient pocket predicted by Molecular Dynamics simulations, which could not be observed from static analysis of CXCL12 PDB structures. The present results indicate how TEMPOL, instrumental in identifying this transient pocket, can be a powerful tool to delineate minor conformations which can be highly relevant in dynamic discovery of antitumoral drugs.
PMID: 24373878 [PubMed - as supplied by publisher]
Searching For Protein Binding Sites From Molecular Dynamics Simulations and Paramagnetic Fragment-based NMR Studies
Searching For Protein Binding Sites From Molecular Dynamics Simulations and Paramagnetic Fragment-based NMR Studies
Publication date: Available online 27 December 2013
Source:Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics</br>
Author(s): Andrea Bernini , Lucia Henrici De Angelis , Edoardo Morandi , Ottavia Spiga , Annalisa Santucci , Michael Assfalg , Henriette Molinari , Serena Pillozzi , Annarosa Arcangeli , Neri Niccolai</br>
Hotspot delineation on protein surfaces represents a fundamental step for targeting protein-protein interfaces....
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Nature. 2011 Jul 24;
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Mitochondrial uncoupling protein 2 (UCP2) is an integral membrane protein in the mitochondrial anion carrier protein family, the members of which facilitate the transport of small molecules across the mitochondrial inner membrane. When the mitochondrial respiratory complex pumps protons from...
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Photoactive yellow protein (PYP) is a...
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Constraining Binding Hot Spots: NMR and Molecular Dynamics Simulations Provide a Stru
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Joshua M. Ward<sup>†</sup>, Nina M. Gorenstein<sup>†</sup>, Jianhua Tian<sup>‡</sup>, Stephen F. Martin<sup>‡</sup> and Carol Beth Post*<sup>†</sup>
Department of Medicinal Chemistry, Markey Center for Structural Biology, and Purdue Cancer Center, Purdue University, West Lafayette, Indiana 47907, and Department of Chemistry and Biochemistry and The Institute of Cellular and Molecular Biology, The University of Texas,...
Searching For Protein Binding Sites From Molecular Dynamics Simulations and Paramagnetic Fragment-based NMR Studies.
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