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Hualiang Jiang - One of the best experts on this subject based on the ideXlab platform.
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mechanism of the all α to all β Conformational Transition of rfah ctd molecular dynamics simulation and markov state model
Journal of Chemical Theory and Computation, 2014Co-Authors: Bing Xiong, Hualiang Jiang, Kaixian Chen, Cheng Luo, Xiaomin Luo, Jingkang Shen, Mingyue ZhengAbstract:The C-terminal domain of the bacterial transcription antiterminator RfaH undergoes a dramatic all-α-helix to all-β-barrel Transition when released from its N-terminal domain. These two distinct folding patterns correspond to different functions: the all-α state acts as an essential regulator of transcription to ensure RNA polymerase binding, whereas the all-β state operates as an activator of translation by interacting with the ribosomal protein S10 and recruits ribosomal mRNA. Accordingly, this drastic Conformational change enables RfaH to physically couple the transcription and translation processes in gene expression. To understand the mechanism behind this extraordinary functionally relevant structural Transition, we constructed Markov state models using an adaptive seeding method. The constructed models highlight several parallel folding pathways with heterogeneous molecular mechanisms, which reveal the folding kinetics and atomic details of the Conformational Transition.
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exploring Transition pathway and free energy profile of large scale protein Conformational change by combining normal mode analysis and umbrella sampling molecular dynamics
Journal of Physical Chemistry B, 2014Co-Authors: Jinan Wang, Qiang Shao, Jiye Shi, Yingtao Liu, Zhuo Yang, Benjamin P Cossins, Hualiang Jiang, Kaixian Chen, Weiliang ZhuAbstract:Large-scale Conformational changes of proteins are usually associated with the binding of ligands. Because the Conformational changes are often related to the biological functions of proteins, understanding the molecular mechanisms of these motions and the effects of ligand binding becomes very necessary. In the present study, we use the combination of normal-mode analysis and umbrella sampling molecular dynamics simulation to delineate the atomically detailed Conformational Transition pathways and the associated free-energy landscapes for three well-known protein systems, viz., adenylate kinase (AdK), calmodulin (CaM), and p38α kinase in the absence and presence of respective ligands. For each protein under study, the transient conformations along the Conformational Transition pathway and thermodynamic observables are in agreement with experimentally and computationally determined ones. The calculated free-energy profiles reveal that AdK and CaM are intrinsically flexible in structures without obvious en...
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Conformational Transition and energy landscape of erbb4 activated by neuregulin1β one microsecond molecular dynamics simulations
Journal of the American Chemical Society, 2012Co-Authors: Huaiyu Yang, Xiaohui Cang, Cheng Luo, Yanyan Mao, Yuanyuan Wang, Guangrong Qin, Xiaomin Luo, Hualiang JiangAbstract:ErbB4, a receptor tyrosine kinase of the ErbB family, plays crucial roles in cell growth and differentiation, especially in the development of the heart and nervous system. Ligand binding to its extracellular region could modulate the activation process. To understand the mechanism of ErbB4 activation induced by ligand binding, we performed one microsecond molecular dynamics (MD) simulations on the ErbB4 extracellular region (ECR) with and without its endogenous ligand neuregulin1β (NRG1β). The Conformational Transition of the ECR-ErbB4/NRG1β complex from a tethered inactive conformation to an extended active-like form has been observed, while such large and function-related Conformational change has not been seen in the simulation on the ECR-ErbB4, suggesting that ligand binding is indeed the active inducing force for the Conformational Transition and further dimerization. On the basis of MD simulations and principal component analysis, we constructed a rough energy landscape for the Conformational Transition of ECR-ErbB4/NRG1β complex, suggesting that the Conformational change from the inactive state to active-like state involves a stable conformation. The energy barrier for the tether opening was estimated as ~2.7 kcal/mol, which is very close to the experimental value (1-2 kcal/mol) reported for ErbB1. On the basis of the simulation results, an atomic mechanism for the ligand-induced activation of ErbB4 was postulated. The present MD simulations provide a new insight into the Conformational changes underlying the activation of ErbB4.
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Conformational Transition pathway in the allosteric process of human glucokinase
Proceedings of the National Academy of Sciences of the United States of America, 2006Co-Authors: Jian Zhang, Weiliang Zhu, Kaixian Chen, Xu Shen, Hualiang JiangAbstract:Glucokinase (GK) is an important enzyme for regulating blood glucose levels and a potentially attractive target for diabetes of the young type 2 and persistent hyperinsulinemic hypoglycemia of infancy. To characterize the Conformational Transition of GK from the closed state to the superopen state, a series of conventional molecular dynamics (MD) and target MD (TMD) simulations were performed on both the wild-type enzyme and its mutants. Two 10-ns conventional MD simulations showed that, although the allosteric site of GK is ≈20 A away from the active site, the activator is able to enhance the activity of the enzyme through Conformational restriction. Fourteen TMD simulations on GK and five of its mutants revealed a reliably Conformational Transition pathway. The overall Conformational Transition includes three stages, and three likely stable intermediate states were identified by free energy scanning for the snapshots throughout the pathway. The Conformational Transition feature revealed by our TMD simulations rationalized several important mutagenesis and kinetic data. Remarkably, the TMD simulations predicted that Y61S, I159A, A201R, V203E, and V452S mutations, which have not been investigated so far, may facilitate the opening process of GK. These predictions also have been verified by mutagenesis and kinetic analyses in this study. These observations are beneficial to understanding the mechanism of GK regulation and designing the compounds for treating metabolic diseases.
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Conformational Transition of amyloid β peptide
Proceedings of the National Academy of Sciences of the United States of America, 2005Co-Authors: Jianhua Shen, Weiliang Zhu, Kaixian Chen, Xiaomin Luo, Hualiang JiangAbstract:The amyloid beta-peptides (Abetas), containing 39-43 residues, are the key protein components of amyloid deposits in Alzheimer's disease. To structurally characterize the dynamic behavior of Abeta(40), 12 independent long-time molecular dynamics (MD) simulations for a total of 850 ns were performed on both the wide-type peptide and its mutant in both aqueous solution and a biomembrane environment. In aqueous solution, an alpha-helix to beta-sheet Conformational Transition for Abeta(40) was observed, and an entire unfolding process from helix to coil was traced by MD simulation. Structures with beta-sheet components were observed as intermediates in the unfolding pathway of Abeta(40). Four glycines (G(25), G(29), G(33), and G(37)) are important for Abeta(40) to form beta-sheet in aqueous solution; mutations of these glycines to alanines almost abolished the beta-sheet formation and increased the content of the helix component. In the dipalmitoyl phosphatidylcholine (DPPC) bilayer, the major secondary structure of Abeta(40) is a helix; however, the peptide tends to exit the membrane environment and lie down on the surface of the bilayer. The dynamic feature revealed by our MD simulations rationalized several experimental observations for Abeta(40) aggregation and amyloid fibril formation. The results of MD simulations are beneficial to understanding the mechanism of amyloid formation and designing the compounds for inhibiting the aggregation of Abeta and amyloid fibril formation.
Akio Kitao - One of the best experts on this subject based on the ideXlab platform.
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Conformational Transition pathway and free energy analyses of proteins by parallel cascade selection molecular dynamics pacs md
INTERNATIONAL CONFERENCE OF COMPUTATIONAL METHODS IN SCIENCES AND ENGINEERING 2014 (ICCMSE 2014), 2014Co-Authors: Ryuhei Harada, Yasutaka Nishihara, Nobuhiko Wakai, Akio KitaoAbstract:Parallel Cascade Selection Molecular Dynamics (PaCS-MD) was recently proposed to generate Conformational Transition pathways of proteins under the condition that a certain target quantity to be reached is introduced (R. Harada and A. Kitao, J. Chem. Phys., 139, 035103 2013). In PaCS-MD, the cycle of short multiple independent molecular dynamics simulations and selection of the structures close to the target quantity for the next cycle are repeated until the simulated structures move sufficiently close to the target. Conformational sampling efficiency is demonstrated in the cases of mini-protein folding/unfolding and protein large Conformational Transitions. The result of PaCS-MD was further utilized to calculate free energy landscape by the combination with weighted-histogram analysis method or Markov state model.
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parallel cascade selection molecular dynamics pacs md to generate Conformational Transition pathway
Journal of Chemical Physics, 2013Co-Authors: Ryuhei Harada, Akio KitaoAbstract:Parallel Cascade Selection Molecular Dynamics (PaCS-MD) is proposed as a molecular simulation method to generate Conformational Transition pathway under the condition that a set of “reactant” and “product” structures is known a priori. In PaCS-MD, the cycle of short multiple independent molecular dynamics simulations and selection of the structures close to the product structure for the next cycle are repeated until the simulated structures move sufficiently close to the product. Folding of 10-residue mini-protein chignolin from the extended to native structures and open-close Conformational Transition of T4 lysozyme were investigated by PaCS-MD. In both cases, tens of cycles of 100-ps MD were sufficient to reach the product structures, indicating the efficient generation of Conformational Transition pathway in PaCS-MD with a series of conventional MD without additional external biases. Using the snapshots along the pathway as the initial coordinates, free energy landscapes were calculated by the combination with multiple independent umbrella samplings to statistically elucidate the Conformational Transition pathways.
Weiliang Zhu - One of the best experts on this subject based on the ideXlab platform.
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Energetics and structural characterization of the "DFG-flip" Conformational Transition of B-RAF kinase: a SITS molecular dynamics study.
Physical chemistry chemical physics : PCCP, 2017Co-Authors: Qiang Shao, Jinan Wang, Jiye Shi, Weiliang ZhuAbstract:B-RAF protein kinase is a promising target to treat malignant melanoma. The kinase activity of B-RAF is regulated by a "DFG-flip" Conformational Transition between functional DFG-in and DFG-out states. The difficulty in resolving the activation loop in crystal structures and the even greater difficulty in experimentally capturing high-energy-level transient structures render elusive the molecular mechanism of the B-RAF functional Conformational Transition. Here, a homology modeling technique and an enhanced sampling molecular dynamics simulation were used to identify and energetically characterize the Conformational Transition pathway of B-RAF on a multi-dimensional free-energy landscape. The results reveal that the Conformational Transition is a two-state Transition, with the evaluated free-energy barrier comparable to those of other kinds of kinases as reported in the previous literature. Hydrophobic interactions between activation loop and neighboring segments are suggested to dominate the Conformational Transition and determine the free-energy barrier. The detailed analysis of hydrophobic interactions involved in the Conformational Transition may show a suitable pathway for the development of the B-RAF inhibitor.
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exploring Transition pathway and free energy profile of large scale protein Conformational change by combining normal mode analysis and umbrella sampling molecular dynamics
Journal of Physical Chemistry B, 2014Co-Authors: Jinan Wang, Qiang Shao, Jiye Shi, Yingtao Liu, Zhuo Yang, Benjamin P Cossins, Hualiang Jiang, Kaixian Chen, Weiliang ZhuAbstract:Large-scale Conformational changes of proteins are usually associated with the binding of ligands. Because the Conformational changes are often related to the biological functions of proteins, understanding the molecular mechanisms of these motions and the effects of ligand binding becomes very necessary. In the present study, we use the combination of normal-mode analysis and umbrella sampling molecular dynamics simulation to delineate the atomically detailed Conformational Transition pathways and the associated free-energy landscapes for three well-known protein systems, viz., adenylate kinase (AdK), calmodulin (CaM), and p38α kinase in the absence and presence of respective ligands. For each protein under study, the transient conformations along the Conformational Transition pathway and thermodynamic observables are in agreement with experimentally and computationally determined ones. The calculated free-energy profiles reveal that AdK and CaM are intrinsically flexible in structures without obvious en...
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Conformational Transition pathway in the allosteric process of human glucokinase
Proceedings of the National Academy of Sciences of the United States of America, 2006Co-Authors: Jian Zhang, Weiliang Zhu, Kaixian Chen, Xu Shen, Hualiang JiangAbstract:Glucokinase (GK) is an important enzyme for regulating blood glucose levels and a potentially attractive target for diabetes of the young type 2 and persistent hyperinsulinemic hypoglycemia of infancy. To characterize the Conformational Transition of GK from the closed state to the superopen state, a series of conventional molecular dynamics (MD) and target MD (TMD) simulations were performed on both the wild-type enzyme and its mutants. Two 10-ns conventional MD simulations showed that, although the allosteric site of GK is ≈20 A away from the active site, the activator is able to enhance the activity of the enzyme through Conformational restriction. Fourteen TMD simulations on GK and five of its mutants revealed a reliably Conformational Transition pathway. The overall Conformational Transition includes three stages, and three likely stable intermediate states were identified by free energy scanning for the snapshots throughout the pathway. The Conformational Transition feature revealed by our TMD simulations rationalized several important mutagenesis and kinetic data. Remarkably, the TMD simulations predicted that Y61S, I159A, A201R, V203E, and V452S mutations, which have not been investigated so far, may facilitate the opening process of GK. These predictions also have been verified by mutagenesis and kinetic analyses in this study. These observations are beneficial to understanding the mechanism of GK regulation and designing the compounds for treating metabolic diseases.
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Conformational Transition of amyloid β peptide
Proceedings of the National Academy of Sciences of the United States of America, 2005Co-Authors: Jianhua Shen, Weiliang Zhu, Kaixian Chen, Xiaomin Luo, Hualiang JiangAbstract:The amyloid beta-peptides (Abetas), containing 39-43 residues, are the key protein components of amyloid deposits in Alzheimer's disease. To structurally characterize the dynamic behavior of Abeta(40), 12 independent long-time molecular dynamics (MD) simulations for a total of 850 ns were performed on both the wide-type peptide and its mutant in both aqueous solution and a biomembrane environment. In aqueous solution, an alpha-helix to beta-sheet Conformational Transition for Abeta(40) was observed, and an entire unfolding process from helix to coil was traced by MD simulation. Structures with beta-sheet components were observed as intermediates in the unfolding pathway of Abeta(40). Four glycines (G(25), G(29), G(33), and G(37)) are important for Abeta(40) to form beta-sheet in aqueous solution; mutations of these glycines to alanines almost abolished the beta-sheet formation and increased the content of the helix component. In the dipalmitoyl phosphatidylcholine (DPPC) bilayer, the major secondary structure of Abeta(40) is a helix; however, the peptide tends to exit the membrane environment and lie down on the surface of the bilayer. The dynamic feature revealed by our MD simulations rationalized several experimental observations for Abeta(40) aggregation and amyloid fibril formation. The results of MD simulations are beneficial to understanding the mechanism of amyloid formation and designing the compounds for inhibiting the aggregation of Abeta and amyloid fibril formation.
Shaojun Dong - One of the best experts on this subject based on the ideXlab platform.
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Conformational Transition of dna induced by cationic lipid vesicle in acidic solution spectroscopy investigation
Biophysical Chemistry, 2002Co-Authors: Zheling Zhang, Weimin Huang, Jilin Tang, Erkang Wang, Shaojun DongAbstract:Abstract The Conformational Transition of DNA induced by the interaction between DNA and a cationic lipid vesicle, didodecyldimethylammonium bromide (DDAB), had been investigated by circular dichroism (CD) and UV spectroscopy methods. We used singular value decomposition least squares method (SVDLS) to analyze the experimental CD spectra. Although pH value influenced the conformation of DNA in solution, the results showed that upon binding to double helical DNA, positively charged liposomes induced a Conformational Transition of DNA molecules from the native B-form to more compact conformations. At the same time, no obvious Conformational changes occurred at single-strand DNA (ssDNA). While the cationic lipid vesicles and double-strand DNA (dsDNA) were mixed at a high molar ratio of DDAB vesicles to dsDNA, the conformation of dsDNA transformed from the B-form to the C-form resulting in an increase in duplex stability (Δ T m =8±0.4 °C). An increasing in T m was also observed while the cationic lipid vesicles interacted with ssDNA.
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Conformational Transition of dna induced by cationic lipid vesicle in acidic solution spectroscopy investigation
Biophysical Chemistry, 2002Co-Authors: Zheling Zhang, Weimin Huang, Jilin Tang, Erkang Wang, Shaojun DongAbstract:The Conformational Transition of DNA induced by the interaction between DNA and a cationic lipid vesicle, didodecyldimethylammonium bromide (DDAB), had been investigated by circular dichroism (CD) and UV spectroscopy methods. We used singular value decomposition least squares method (SVDLS) to analyze the experimental CD spectra. Although pH value influenced the conformation of DNA in solution, the results showed that upon binding to double helical DNA, positively charged liposomes induced a Conformational Transition of DNA molecules from the native B-form to more compact conformations. At the same time, no obvious Conformational changes occurred at single-strand DNA (ssDNA). While the cationic lipid vesicles and double-strand DNA (dsDNA) were mixed at a high molar ratio of DDAB vesicles to dsDNA, the conformation of dsDNA transformed from the B-form to the C-form resulting in an increase in duplex stability (DeltaT(m)=8+/-0.4 degrees C). An increasing in T(m) was also observed while the cationic lipid vesicles interacted with ssDNA.
Antonio Monari - One of the best experts on this subject based on the ideXlab platform.
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the iron maiden cytosolic aconitase irp1 Conformational Transition in the regulation of ferritin translation and iron hemostasis
Biomolecules, 2021Co-Authors: Cecilia Hognon, Emmanuelle Bignon, Guillaume Harle, Nadege Touche, Stephanie Grandemange, Antonio MonariAbstract:Maintaining iron homeostasis is fundamental for almost all living beings, and its deregulation correlates with severe and debilitating pathologies. The process is made more complicated by the omnipresence of iron and by its role as a fundamental component of a number of crucial metallo proteins. The response to modifications in the amount of the free-iron pool is performed via the inhibition of ferritin translation by sequestering consensus messenger RNA (mRNA) sequences. In turn, this is regulated by the iron-sensitive Conformational equilibrium between cytosolic aconitase and IRP1, mediated by the presence of an iron-sulfur cluster. In this contribution, we analyze by full-atom molecular dynamics simulation, the factors leading to both the interaction with mRNA and the Conformational Transition. Furthermore, the role of the iron-sulfur cluster in driving the Conformational Transition is assessed by obtaining the related free energy profile via enhanced sampling molecular dynamics simulations.
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The Iron Maiden. Cytosolic Aconitase/IRP1 Conformational Transition in the Regulation of Ferritin Translation and Iron Hemostasis
'MDPI AG', 2021Co-Authors: Cecilia Hognon, Emmanuelle Bignon, Guillaume Harle, Nadege Touche, Stephanie Grandemange, Antonio MonariAbstract:Maintaining iron homeostasis is fundamental for almost all living beings, and its deregulation correlates with severe and debilitating pathologies. The process is made more complicated by the omnipresence of iron and by its role as a fundamental component of a number of crucial metallo proteins. The response to modifications in the amount of the free-iron pool is performed via the inhibition of ferritin translation by sequestering consensus messenger RNA (mRNA) sequences. In turn, this is regulated by the iron-sensitive Conformational equilibrium between cytosolic aconitase and IRP1, mediated by the presence of an iron–sulfur cluster. In this contribution, we analyze by full-atom molecular dynamics simulation, the factors leading to both the interaction with mRNA and the Conformational Transition. Furthermore, the role of the iron–sulfur cluster in driving the Conformational Transition is assessed by obtaining the related free energy profile via enhanced sampling molecular dynamics simulations