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 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 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 Optimization of Molecular Dynamics Simulations of c-MYC1-88—An Intrinsically Disordered System

Life ◽  
2020 ◽  
Vol 10 (7) ◽  
pp. 109 ◽  
Author(s):  
Sandra S. Sullivan ◽  
Robert O.J. Weinzierl
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulations ◽  
Intrinsically Disordered Proteins ◽  
Disordered Proteins ◽  
Intrinsically Disordered ◽  
Intrinsically Disordered Regions ◽  
Proliferation And Apoptosis ◽  
Conventional Structure ◽  
Experimental Approaches ◽  
Dynamics Simulations

Many of the proteins involved in key cellular regulatory events contain extensive intrinsically disordered regions that are not readily amenable to conventional structure/function dissection. The oncoprotein c-MYC plays a key role in controlling cell proliferation and apoptosis and more than 70% of the primary sequence is disordered. Computational approaches that shed light on the range of secondary and tertiary structural conformations therefore provide the only realistic chance to study such proteins. Here, we describe the results of several tests of force fields and water models employed in molecular dynamics simulations for the N-terminal 88 amino acids of c-MYC. Comparisons of the simulation data with experimental secondary structure assignments obtained by NMR establish a particular implicit solvation approach as highly congruent. The results provide insights into the structural dynamics of c-MYC1-88, which will be useful for guiding future experimental approaches. The protocols for trajectory analysis described here will be applicable for the analysis of a variety of computational simulations of intrinsically disordered proteins.

scholarly journals Different force fields give rise to different amyloid aggregation pathways in molecular dynamics simulations

2020 ◽  
Author(s):  
Suman Samantray ◽  
Feng Yin ◽  
Batuhan Kav ◽  
Birgit Strodel
Keyword(s):  
Molecular Dynamics ◽  
Force Field ◽  
Intrinsically Disordered Proteins ◽  
Force Fields ◽  
Md Simulations ◽  
Peptide Sequence ◽  
Disordered Proteins ◽  
Test Case ◽  
Peptide Aggregation ◽  
Intrinsically Disordered

AbstractThe progress towards understanding the molecular basis of Alzheimers’s disease is strongly connected to elucidating the early aggregation events of the amyloid-β (Aβ) peptide. Molecular dynamics (MD) simulations provide a viable technique to study the aggregation of Aβ into oligomers with high spatial and temporal resolution. However, the results of an MD simulation can only be as good as the underlying force field. A recent study by our group showed that none of the force fields tested can distinguish between aggregation-prone and non-aggregating peptide sequences, producing the same and in most cases too fast aggregation kinetics for all peptides. Since then, new force fields specially designed for intrinsically disordered proteins such as Aβ were developed. Here, we assess the applicability of these new force fields to studying peptide aggregation using the Aβ16−22 peptide and mutations of it as test case. We investigate their performance in modeling the monomeric state, the aggregation into oligomers, and the stability of the aggregation end product, i.e., the fibrillar state. A main finding is that changing the force field has a stronger effect on the simulated aggregation pathway than changing the peptide sequence. Also the new force fields are not able to reproduce the experimental aggregation propensity order of the peptides. Dissecting the various energy contributions shows that AMBER99SB-disp overestimates the interactions between the peptides and water, thereby inhibiting peptide aggregation. More promising results are obtained with CHARMM36m and especially its version with increased protein–water interactions. It is thus recommended to use this force field for peptide aggregation simulations and base future reparameterizations on it.

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 Generation of the configurational ensemble of an intrinsically disordered protein from unbiased molecular dynamics simulation

2019 ◽  
Vol 116 (41) ◽  
pp. 20446-20452 ◽  
Author(s):  
Utsab R. Shrestha ◽  
Puneet Juneja ◽  
Qiu Zhang ◽  
Viswanathan Gurumoorthy ◽  
Jose M. Borreguero ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Intrinsically Disordered Proteins ◽  
Chemical Shifts ◽  
Intrinsically Disordered Protein ◽  
Physical Models ◽  
Dynamics Simulation ◽  
Disordered Proteins ◽  
Intrinsically Disordered ◽  
Eukaryotic Proteomes ◽  
Heterogeneous Ensemble

Intrinsically disordered proteins (IDPs) are abundant in eukaryotic proteomes, play a major role in cell signaling, and are associated with human diseases. To understand IDP function it is critical to determine their configurational ensemble, i.e., the collection of 3-dimensional structures they adopt, and this remains an immense challenge in structural biology. Attempts to determine this ensemble computationally have been hitherto hampered by the necessity of reweighting molecular dynamics (MD) results or biasing simulation in order to match ensemble-averaged experimental observables, operations that reduce the precision of the generated model because different structural ensembles may yield the same experimental observable. Here, by employing enhanced sampling MD we reproduce the experimental small-angle neutron and X-ray scattering profiles and the NMR chemical shifts of the disordered N terminal (SH4UD) of c-Src kinase without reweighting or constraining the simulations. The unbiased simulation results reveal a weakly funneled and rugged free energy landscape of SH4UD, which gives rise to a heterogeneous ensemble of structures that cannot be described by simple polymer theory. SH4UD adopts transient helices, which are found away from known phosphorylation sites and could play a key role in the stabilization of structural regions necessary for phosphorylation. Our findings indicate that adequately sampled molecular simulations can be performed to provide accurate physical models of flexible biosystems, thus rationalizing their biological function.

scholarly journals Molecular dynamics simulations and CD spectroscopy reveal hydration-induced unfolding of the intrinsically disordered LEA proteins COR15A and COR15B from Arabidopsis thaliana

2016 ◽  
Vol 18 (37) ◽  
pp. 25806-25816 ◽  
Author(s):  
Carlos Navarro-Retamal ◽  
Anne Bremer ◽  
Jans Alzate-Morales ◽  
Julio Caballero ◽  
Dirk K. Hincha ◽  
...  
Keyword(s):  
Experimental Data ◽  
Molecular Dynamics ◽  
Arabidopsis Thaliana ◽  
Molecular Dynamics Simulations ◽  
Md Simulations ◽  
Cd Spectroscopy ◽  
Lea Proteins ◽  
Intrinsically Disordered ◽  
Dynamics Simulations ◽  
Crowded Environment

Unfolding of intrinsically unstructured full-length LEA proteins in a differentially crowded environment can be modeled by 30 ns MD simulations in accordance with experimental data.

scholarly journals Intrinsically disordered proteins identified in the aggregate proteome serve as biomarkers of neurodegeneration

2021 ◽  
Author(s):  
Srinivas Ayyadevara ◽  
Akshatha Ganne ◽  
Meenakshisundaram Balasubramaniam ◽  
Robert J. Shmookler Reis
Keyword(s):  
Intrinsically Disordered Proteins ◽  
Protein Complexes ◽  
Disordered Proteins ◽  
Intrinsically Disordered ◽  
Intrinsically Disordered Regions ◽  
Physiological Processes ◽  
Protein Partners ◽  
And Function ◽  
Computational Analyses ◽  
Disordered Regions

AbstractA protein’s structure is determined by its amino acid sequence and post-translational modifications, and provides the basis for its physiological functions. Across all organisms, roughly a third of the proteome comprises proteins that contain highly unstructured or intrinsically disordered regions. Proteins comprising or containing extensive unstructured regions are referred to as intrinsically disordered proteins (IDPs). IDPs are believed to participate in complex physiological processes through refolding of IDP regions, dependent on their binding to a diverse array of potential protein partners. They thus play critical roles in the assembly and function of protein complexes. Recent advances in experimental and computational analyses predicted multiple interacting partners for the disordered regions of proteins, implying critical roles in signal transduction and regulation of biological processes. Numerous disordered proteins are sequestered into aggregates in neurodegenerative diseases such as Alzheimer’s disease (AD) where they are enriched even in serum, making them good candidates for serum biomarkers to enable early detection of AD.

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