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Molecular Dynamics Investigations Suggest a Non-specific Recognition Strategy of 14-3-3σ Protein by Tweezer: Implication for the Inhibition Mechanism

The supramolecular complex formed between protein and designed molecule has become one of the most efficient ways to modify protein functions. As one of the more well-studied model systems, 14-3-3 family proteins play an important role in regulating intracellular signaling pathways via protein-prote...

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Autores principales: Shi, Mingsong, Xu, Dingguo
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6478809/
https://www.ncbi.nlm.nih.gov/pubmed/31058132
http://dx.doi.org/10.3389/fchem.2019.00237
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author Shi, Mingsong
Xu, Dingguo
author_facet Shi, Mingsong
Xu, Dingguo
author_sort Shi, Mingsong
collection PubMed
description The supramolecular complex formed between protein and designed molecule has become one of the most efficient ways to modify protein functions. As one of the more well-studied model systems, 14-3-3 family proteins play an important role in regulating intracellular signaling pathways via protein-protein interactions. In this work, we selected 14-3-3σ as the target protein. Molecular dynamics simulations and binding free energy calculations were applied to identify the possible binding sites and understand its recognition ability of the supramolecular inhibitor, the tweezer molecule (CLR01). On the basis of our simulation, major interactions between lysine residues and CLR01 come from the van der Waals interactions between the long alkyl chain of lysine and the cavity formed by the norbornadiene and benzene rings of the inhibitor. Apart from K214, which was found to be crystallized with this inhibitor, other lysine sites have also shown their abilities to form inclusion complexes with the inhibitor. Such non-specific recognition features of CLR01 against 14-3-3σ can be used in the modification of protein functions via supramolecular chemistry.
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spelling pubmed-64788092019-05-03 Molecular Dynamics Investigations Suggest a Non-specific Recognition Strategy of 14-3-3σ Protein by Tweezer: Implication for the Inhibition Mechanism Shi, Mingsong Xu, Dingguo Front Chem Chemistry The supramolecular complex formed between protein and designed molecule has become one of the most efficient ways to modify protein functions. As one of the more well-studied model systems, 14-3-3 family proteins play an important role in regulating intracellular signaling pathways via protein-protein interactions. In this work, we selected 14-3-3σ as the target protein. Molecular dynamics simulations and binding free energy calculations were applied to identify the possible binding sites and understand its recognition ability of the supramolecular inhibitor, the tweezer molecule (CLR01). On the basis of our simulation, major interactions between lysine residues and CLR01 come from the van der Waals interactions between the long alkyl chain of lysine and the cavity formed by the norbornadiene and benzene rings of the inhibitor. Apart from K214, which was found to be crystallized with this inhibitor, other lysine sites have also shown their abilities to form inclusion complexes with the inhibitor. Such non-specific recognition features of CLR01 against 14-3-3σ can be used in the modification of protein functions via supramolecular chemistry. Frontiers Media S.A. 2019-04-17 /pmc/articles/PMC6478809/ /pubmed/31058132 http://dx.doi.org/10.3389/fchem.2019.00237 Text en Copyright © 2019 Shi and Xu. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Chemistry
Shi, Mingsong
Xu, Dingguo
Molecular Dynamics Investigations Suggest a Non-specific Recognition Strategy of 14-3-3σ Protein by Tweezer: Implication for the Inhibition Mechanism
title Molecular Dynamics Investigations Suggest a Non-specific Recognition Strategy of 14-3-3σ Protein by Tweezer: Implication for the Inhibition Mechanism
title_full Molecular Dynamics Investigations Suggest a Non-specific Recognition Strategy of 14-3-3σ Protein by Tweezer: Implication for the Inhibition Mechanism
title_fullStr Molecular Dynamics Investigations Suggest a Non-specific Recognition Strategy of 14-3-3σ Protein by Tweezer: Implication for the Inhibition Mechanism
title_full_unstemmed Molecular Dynamics Investigations Suggest a Non-specific Recognition Strategy of 14-3-3σ Protein by Tweezer: Implication for the Inhibition Mechanism
title_short Molecular Dynamics Investigations Suggest a Non-specific Recognition Strategy of 14-3-3σ Protein by Tweezer: Implication for the Inhibition Mechanism
title_sort molecular dynamics investigations suggest a non-specific recognition strategy of 14-3-3σ protein by tweezer: implication for the inhibition mechanism
topic Chemistry
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6478809/
https://www.ncbi.nlm.nih.gov/pubmed/31058132
http://dx.doi.org/10.3389/fchem.2019.00237
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