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The Observation of Ligand-Binding-Relevant Open States of Fatty Acid Binding Protein by Molecular Dynamics Simulations and a Markov State Model

As a member of the fatty acids transporter family, the heart fatty acid binding proteins (HFABPs) are responsible for many important biological activities. The binding mechanism of fatty acid with FABP is critical to the understanding of FABP functions. The uncovering of binding-relevant intermediat...

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Autores principales: Guo, Yue, Duan, Mojie, Yang, Minghui
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6678811/
https://www.ncbi.nlm.nih.gov/pubmed/31311155
http://dx.doi.org/10.3390/ijms20143476
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author Guo, Yue
Duan, Mojie
Yang, Minghui
author_facet Guo, Yue
Duan, Mojie
Yang, Minghui
author_sort Guo, Yue
collection PubMed
description As a member of the fatty acids transporter family, the heart fatty acid binding proteins (HFABPs) are responsible for many important biological activities. The binding mechanism of fatty acid with FABP is critical to the understanding of FABP functions. The uncovering of binding-relevant intermediate states and interactions would greatly increase our knowledge of the binding process. In this work, all-atom molecular dynamics (MD) simulations were performed to characterize the structural properties of nativelike intermediate states. Based on multiple 6 μs MD simulations and Markov state model (MSM) analysis, several “open” intermediate states were observed. The transition rates between these states and the native closed state are in good agreement with the experimental measurements, which indicates that these intermediate states are binding relevant. As a common property in the open states, the partially unfolded α2 helix generates a larger portal and provides the driving force to facilitate ligand binding. On the other side, there are two kinds of open states for the ligand-binding HFABP: one has the partially unfolded α2 helix, and the other has the looser β-barrel with disjointing βD-βE strands. Our results provide atomic-level descriptions of the binding-relevant intermediate states and could improve our understanding of the binding mechanism.
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spelling pubmed-66788112019-08-19 The Observation of Ligand-Binding-Relevant Open States of Fatty Acid Binding Protein by Molecular Dynamics Simulations and a Markov State Model Guo, Yue Duan, Mojie Yang, Minghui Int J Mol Sci Article As a member of the fatty acids transporter family, the heart fatty acid binding proteins (HFABPs) are responsible for many important biological activities. The binding mechanism of fatty acid with FABP is critical to the understanding of FABP functions. The uncovering of binding-relevant intermediate states and interactions would greatly increase our knowledge of the binding process. In this work, all-atom molecular dynamics (MD) simulations were performed to characterize the structural properties of nativelike intermediate states. Based on multiple 6 μs MD simulations and Markov state model (MSM) analysis, several “open” intermediate states were observed. The transition rates between these states and the native closed state are in good agreement with the experimental measurements, which indicates that these intermediate states are binding relevant. As a common property in the open states, the partially unfolded α2 helix generates a larger portal and provides the driving force to facilitate ligand binding. On the other side, there are two kinds of open states for the ligand-binding HFABP: one has the partially unfolded α2 helix, and the other has the looser β-barrel with disjointing βD-βE strands. Our results provide atomic-level descriptions of the binding-relevant intermediate states and could improve our understanding of the binding mechanism. MDPI 2019-07-15 /pmc/articles/PMC6678811/ /pubmed/31311155 http://dx.doi.org/10.3390/ijms20143476 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Guo, Yue
Duan, Mojie
Yang, Minghui
The Observation of Ligand-Binding-Relevant Open States of Fatty Acid Binding Protein by Molecular Dynamics Simulations and a Markov State Model
title The Observation of Ligand-Binding-Relevant Open States of Fatty Acid Binding Protein by Molecular Dynamics Simulations and a Markov State Model
title_full The Observation of Ligand-Binding-Relevant Open States of Fatty Acid Binding Protein by Molecular Dynamics Simulations and a Markov State Model
title_fullStr The Observation of Ligand-Binding-Relevant Open States of Fatty Acid Binding Protein by Molecular Dynamics Simulations and a Markov State Model
title_full_unstemmed The Observation of Ligand-Binding-Relevant Open States of Fatty Acid Binding Protein by Molecular Dynamics Simulations and a Markov State Model
title_short The Observation of Ligand-Binding-Relevant Open States of Fatty Acid Binding Protein by Molecular Dynamics Simulations and a Markov State Model
title_sort observation of ligand-binding-relevant open states of fatty acid binding protein by molecular dynamics simulations and a markov state model
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6678811/
https://www.ncbi.nlm.nih.gov/pubmed/31311155
http://dx.doi.org/10.3390/ijms20143476
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