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Exploring Anion-Induced Conformational Flexibility and Molecular Switching in a Series of Heteroaryl-Urea Receptors.

ABSTRACT: Anion binding studies of 1,10-phenanthroline- and 2-pyridyl-substituted urea-based receptors reveal that guest-dependent conformations exist in structural variants related to a previously investigated bipyridyl-based receptor. Dynamic conformational switching persists in a monofunctional pyridyl-urea receptor, and the preorganization provided by a phenanthroline-based analogue promotes convergence of anion coordinating groups to a single guest. Despite this predisposition for anion coordination, the conformational flexibility of the bipyridyl-based receptor provides the most selective motif for H₂PO₄^- coordination. Furthermore, the two new phenanthrolyl- and pyridyl-receptors serve as models of the bipyridyl-based receptor, elucidating accurate stepwise association constants for 1:2 host/guest binding by this receptor, and suggest that oxoanions prefer the embrace of a "U" conformation in 1:1 complexes.

SUBMITTER: Gavette JV

PROVIDER: S-EPMC4068745 | biostudies-literature | 2014 Jul

REPOSITORIES: biostudies-literature

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Exploring Anion-Induced Conformational Flexibility and Molecular Switching in a Series of Heteroaryl-Urea Receptors.

Gavette Jesse V JV Evoniuk Christopher J CJ Zakharov Lev N LN Carnes Matthew E ME Haley Michael M MM Johnson Darren W DW

Chemical science 20140701 7

Anion binding studies of 1,10-phenanthroline- and 2-pyridyl-substituted urea-based receptors reveal that guest-dependent conformations exist in structural variants related to a previously investigated bipyridyl-based receptor. Dynamic conformational switching persists in a monofunctional pyridyl-urea receptor, and the preorganization provided by a phenanthroline-based analogue promotes convergence of anion coordinating groups to a single guest. Despite this predisposition for anion coordination, ...[more]

PMID: 24976946

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Project description:Intrinsically disordered proteins represent a class of proteins that lack fixed and well-defined three-dimensional structures in solution. HIV-1 Nef is an intrinsically disordered peripheral membrane protein involved in the replication and pathogenesis of HIV-1 infection. Nef controls expression levels of cell surface CD4 molecules that are essential for adaptive immunity. Despite the lack of fixed and stable structures, Nef physically interacts with the host cellular proteins (AP-1/MHC-I) and modulates intracellular trafficking pathways. Therefore, it is essential to understand how this dynamic conformational flexibility affects Nef structures and function. In this study, we combined all-atom molecular dynamics (MD) simulations and dynamic network approaches to better understand the structure and dynamics of Nef in two different forms, the free unbound and the bound state. Using the MD simulation approach, we show that the intrinsically disordered Nef exhibit a large dynamic field with more atomic fluctuations and lesser thermodynamic stability in the unbound conditions. The conformations of Nef change over time, and this protein remains more compact, folded, and stable in the bound form. The dynamic network analysis revealed regions of the protein capable of modulating the conformational behavior of the disordered Nef. The average betweenness centrality (BC) unveiled residues that are critical for mediating protein-protein interactions. The average shortest path length (L) and the perturbation response scanning exposed residues that are likely to be important in steering protein conformational changes. Overall, the study demonstrates how all-atom MD simulations combined with the dynamic network approach can be used to gain further insights into the structure and dynamics-function relationship of intrinsically disordered HIV-1 Nef.Supplementary informationThe online version contains supplementary material available at 10.1007/s13205-021-02698-8.

Dataset Information

Exploring Anion-Induced Conformational Flexibility and Molecular Switching in a Series of Heteroaryl-Urea Receptors.

Publications

Exploring Anion-Induced Conformational Flexibility and Molecular Switching in a Series of Heteroaryl-Urea Receptors.

Similar Datasets

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