scholarly journals Integrating an Enhanced Sampling Method and Small-Angle X-Ray Scattering to Study Intrinsically Disordered Proteins

2021 ◽  
Vol 8 ◽  
Author(s):  
Chengtao Ding ◽  
Sheng Wang ◽  
Zhiyong Zhang
Keyword(s):  
Experimental Data ◽  
Small Angle ◽  
Sampling Method ◽  
Intrinsically Disordered Proteins ◽  
Md Simulations ◽  
Disordered Proteins ◽  
Enhanced Sampling ◽  
X Ray ◽  
Intrinsically Disordered ◽  
X Ray Scattering

Intrinsically disordered proteins (IDPs) have been paid more and more attention over the past decades because they are involved in a multitude of crucial biological functions. Despite their functional importance, IDPs are generally difficult to investigate because they are very flexible and lack stable structures. Computer simulation may serve as a useful tool in studying IDPs. With the development of computer software and hardware, computational methods, such as molecular dynamics (MD) simulations, are popularly used. However, there is a sampling problem in MD simulations. In this work, this issue is investigated using an IDP called unique long region 11 (UL11), which is the conserved outer tegument component from herpes simplex virus 1. After choosing a proper force field and water model that is suitable for simulating IDPs, integrative modeling by combining an enhanced sampling method and experimental data like small-angle X-ray scattering (SAXS) is utilized to efficiently sample the conformations of UL11. The simulation results are in good agreement with experimental data. This work may provide a general protocol to study structural ensembles of IDPs.

scholarly journals Development of Charge-Augmented Three-Point Water Model (CAIPi3P) for Accurate Simulations of Intrinsically Disordered Proteins

2019 ◽  
Author(s):  
Joao Victor de Souza Cunha ◽  
Francesc Sabanes Zariquiey ◽  
Agnieszka K. Bronowska
Keyword(s):  
Experimental Data ◽  
Molecular Dynamics ◽  
Intrinsically Disordered Proteins ◽  
Md Simulations ◽  
Disordered Proteins ◽  
Water Model ◽  
High Plasticity ◽  
Solvation Model ◽  
Intrinsically Disordered ◽  
Intrinsically Disordered Regions

Intrinsically disordered proteins (IDPs) are molecules without a fixed tertiary structure, exerting crucial roles in cellular signalling, growth and molecular recognition events. Due to their high plasticity, IDPs are very challenging in experimental and computational structural studies. To provide detailed atomic insight in IDPs dynamics governing its functional mechanisms, all-atom molecular dynamics (MD) simulations are widely employed. However, the current generalist force fields and solvent models are unable to generate satisfactory ensembles for IDPs when compared to existing experimental data. In this work, we present a new solvation model, denoted as Charge-Augmented 3 Point Water model for Intrinsically-disordered Proteins (CAIPi3P). CAIPi3P has been generated by performing a systematic scanning of atomic partial charges assigned to the widely popular molecular scaffold of the three-point TIP3P water model. We found that explicit solvent MD simulations employing CAIPi3P solvation considerably improved the SAXS scattering profiles for three different IDPs. Not surprisingly, this improvement was further enhanced by using CAIPi3P water in combination with the protein force field parametrized for IDPs. We have also demonstrated applicability of CAIPi3P to molecular systems containing structured as well as intrinsically disordered regions/domains. Our results highlight the crucial importance of solvent effects for generating molecular ensembles of IDPs which reproduce the experimental data available. Hence, we conclude that our newly developed CAIPi3P solvation model is a valuable tool assisting molecular simulations of intrinsically disordered proteins and assessing their molecular dynamics.

scholarly journals Architecture and subunit dynamics of the mitochondrial TIM9·10·12 chaperone

2020 ◽  
Author(s):  
Katharina Weinhäupl ◽  
Yong Wang ◽  
Audrey Hessel ◽  
Martha Brennich ◽  
Kresten Lindorff-Larsen ◽  
...  
Keyword(s):  
Md Simulation ◽  
Structural Model ◽  
Intrinsically Disordered Proteins ◽  
Disordered Proteins ◽  
Free Form ◽  
X Ray ◽  
Intrinsically Disordered ◽  
X Ray Scattering ◽  
Exchange Kinetics ◽  
Binding Groove

The mitochondrial Tim chaperones are responsible for the transport of membrane proteins across the inter-membrane space to the inner and outer mitochondrial membranes. TIM9·10, a hexameric 70 kDa protein complex formed by 3 copies of Tim9 and Tim10, guides its clients across the aqueous compartment. The TIM9·10·12 complex is the anchor point at the inner-membrane insertase complex TIM22. The mechanism of client transport by TIM9·10 has been resolved recently, but the structure and subunit composition of the TIM9·10·12 complex remains largely unresolved. Furthermore, the assembly process of the hexameric TIM chaperones from its subunits remained elusive. We investigate the structural and dynamical properties of the Tim subunits, and show that they are highly dynamic. In their non-assembled form, the subunits behave as intrinsically disordered proteins; when the conserved cysteines of the CX3C-Xn-CX3C motifs are formed, short marginally stable α-helices are formed, which are only fully stabilized upon hexamer formation to the mature chaperone. Subunits are in equilibrium between their hexamer-embedded and a free form, with exchange kinetics on a minutes time scale. Joint NMR, small-angle X-ray scattering and MD simulation data allow us to derive a structural model of the TIM9·10·12 assembly, which has a 2:3:1 stoichiometry (Tim9:Tim10:Tim12) with a conserved hydrophobic client-binding groove and flexible N- and C-terminal tentacles.

scholarly journals Development of Charge-Augmented Three-Point Water Model (CAIPi3P) for Accurate Simulations of Intrinsically Disordered Proteins

2020 ◽  
Vol 21 (17) ◽  
pp. 6166
Author(s):  
Joao V. de Souza ◽  
Francesc Sabanés Zariquiey ◽  
Agnieszka K. Bronowska
Keyword(s):  
Experimental Data ◽  
Molecular Dynamics ◽  
Intrinsically Disordered Proteins ◽  
Md Simulations ◽  
Disordered Proteins ◽  
Water Model ◽  
High Plasticity ◽  
Solvation Model ◽  
Intrinsically Disordered ◽  
Intrinsically Disordered Regions

Intrinsically disordered proteins (IDPs) are molecules without a fixed tertiary structure, exerting crucial roles in cellular signalling, growth and molecular recognition events. Due to their high plasticity, IDPs are very challenging in experimental and computational structural studies. To provide detailed atomic insight in IDPs’ dynamics governing their functional mechanisms, all-atom molecular dynamics (MD) simulations are widely employed. However, the current generalist force fields and solvent models are unable to generate satisfactory ensembles for IDPs when compared to existing experimental data. In this work, we present a new solvation model, denoted as the Charge-Augmented Three-Point Water Model for Intrinsically Disordered Proteins (CAIPi3P). CAIPi3P has been generated by performing a systematic scan of atomic partial charges assigned to the widely popular molecular scaffold of the three-point TIP3P water model. We found that explicit solvent MD simulations employing CAIPi3P solvation considerably improved the small-angle X-ray scattering (SAXS) scattering profiles for three different IDPs. Not surprisingly, this improvement was further enhanced by using CAIPi3P water in combination with the protein force field parametrized for IDPs. We also demonstrated the applicability of CAIPi3P to molecular systems containing structured as well as intrinsically disordered regions/domains. Our results highlight the crucial importance of solvent effects for generating molecular ensembles of IDPs which reproduce the experimental data available. Hence, we conclude that our newly developed CAIPi3P solvation model is a valuable tool for molecular simulations of intrinsically disordered proteins and assessing their molecular dynamics.

scholarly journals Dynamical Oligomerisation of Histidine Rich Intrinsically Disordered Proteins Is Regulated through Zinc-Histidine Interactions

Biomolecules ◽  
2019 ◽  
Vol 9 (5) ◽  
pp. 168 ◽  
Author(s):  
Carolina Cragnell ◽  
Lasse Staby ◽  
Samuel Lenton ◽  
Birthe Kragelund ◽  
Marie Skepö
Keyword(s):  
Nuclear Magnetic Resonance ◽  
Intrinsically Disordered Proteins ◽  
Divalent Cations ◽  
Disordered Proteins ◽  
Resonance Spectroscopy ◽  
Binding Motifs ◽  
Histatin 5 ◽  
X Ray ◽  
Intrinsically Disordered ◽  
X Ray Scattering

Intrinsically disordered proteins (IDPs) can form functional oligomers and in some cases, insoluble disease related aggregates. It is therefore vital to understand processes and mechanisms that control pathway distribution. Divalent cations including Zn2+ can initiate IDP oligomerisation through the interaction with histidine residues but the mechanisms of doing so are far from understood. Here we apply a multi-disciplinary approach using small angle X-ray scattering, nuclear magnetic resonance spectroscopy, calorimetry and computations to show that that saliva protein Histatin 5 forms highly dynamic oligomers in the presence of Zn2+. The process is critically dependent upon interaction between Zn2+ ions and distinct histidine rich binding motifs which allows for thermodynamic switching between states. We propose a molecular mechanism of oligomerisation, which may be generally applicable to other histidine rich IDPs. Finally, as Histatin 5 is an important saliva component, we suggest that Zn2+ induced oligomerisation may be crucial for maintaining saliva homeostasis.

scholarly journals Improving the global dimensions of intrinsically disordered proteins in Martini 3

2021 ◽  
Author(s):  
F. Emil Thomasen ◽  
Francesco Pesce ◽  
Mette Ahrensback Roesgaard ◽  
Giulio Tesei ◽  
Kresten Lindorff-Larsen
Keyword(s):  
Molecular Dynamics ◽  
Intrinsically Disordered Proteins ◽  
Coarse Grained ◽  
Disordered Proteins ◽  
Saxs Data ◽  
X Ray ◽  
Conformational Ensembles ◽  
Intrinsically Disordered ◽  
X Ray Scattering ◽  
Dynamics Simulations

AbstractCoarse-grained molecular dynamics simulations are a useful tool to determine conformational ensembles of intrinsically disordered proteins (IDPs). Here, we show that the coarse-grained force field Martini 3 underestimates the global dimensions of IDPs when compared with small angle X-ray scattering (SAXS) data. Increasing the strength of protein-water interactions favors more expanded conformations, improving agreement with SAXS data and alleviating problems with overestimated IDP-IDP interactions.

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