scholarly journals Refinement of α-Synuclein Ensembles Against SAXS Data: Comparison of Force Fields and Methods

2021 ◽  
Vol 8 ◽  
Author(s):  
Mustapha Carab Ahmed ◽  
Line K. Skaanning ◽  
Alexander Jussupow ◽  
Estella A. Newcombe ◽  
Birthe B. Kragelund ◽  
...  
Keyword(s):  
Experimental Data ◽  
Force Field ◽  
Intrinsically Disordered Proteins ◽  
Force Fields ◽  
The Other ◽  
Disordered Proteins ◽  
Saxs Data ◽  
Intrinsically Disordered ◽  
Other Hand ◽  
Dynamics Simulations

The inherent flexibility of intrinsically disordered proteins (IDPs) makes it difficult to interpret experimental data using structural models. On the other hand, molecular dynamics simulations of IDPs often suffer from force-field inaccuracies, and long simulation times or enhanced sampling methods are needed to obtain converged ensembles. Here, we apply metainference and Bayesian/Maximum Entropy reweighting approaches to integrate prior knowledge of the system with experimental data, while also dealing with various sources of errors and the inherent conformational heterogeneity of IDPs. We have measured new SAXS data on the protein α-synuclein, and integrate this with simulations performed using different force fields. We find that if the force field gives rise to ensembles that are much more compact than what is implied by the SAXS data it is difficult to recover a reasonable ensemble. On the other hand, we show that when the simulated ensemble is reasonable, we can obtain an ensemble that is consistent with the SAXS data, but also with NMR diffusion and paramagnetic relaxation enhancement data.

scholarly journals Refinement of α-synuclein ensembles against SAXS data: Comparison of force fields and methods

2021 ◽  
Author(s):  
Mustapha Carab Ahmed ◽  
Line K. Skaanning ◽  
Alexander Jussupow ◽  
Estella A. Newcombe ◽  
Birthe B. Kragelund ◽  
...  
Keyword(s):  
Experimental Data ◽  
Force Field ◽  
Intrinsically Disordered Proteins ◽  
Force Fields ◽  
The Other ◽  
Disordered Proteins ◽  
Saxs Data ◽  
Intrinsically Disordered ◽  
Other Hand ◽  
Dynamics Simulations

AbstractThe inherent flexibility of intrinsically disordered proteins (IDPs) makes it difficult to interpret experimental data using structural models. On the other hand, molecular dynamics simulations of IDPs often suffer from force-field inaccuracies, and long simulations times or enhanced sampling methods are needed to obtain converged ensembles. Here, we apply metainference and Bayesian/Maximum Entropy reweighting approaches to integrate prior knowledge of the system with experimental data, while also dealing with various sources of errors and the inherent conformational heterogeneity of IDPs. We have measured new SAXS data on the protein α-synuclein, and integrate this with simulations performed using different force fields. We find that if the force field gives rise to ensembles that are much more compact than what is implied by the SAXS data it is difficult to recover a reasonable ensemble. On the other hand, we show that when the simulated ensemble is reasonable, we can obtain an ensemble that is consistent with the SAXS data, but also with NMR diffusion and paramagnetic relaxation enhancement data.

scholarly journals Bayesian inference of protein ensembles from SAXS data

2016 ◽  
Vol 18 (8) ◽  
pp. 5832-5838 ◽  
Author(s):  
L. D. Antonov ◽  
S. Olsson ◽  
W. Boomsma ◽  
T. Hamelryck
Keyword(s):  
Bayesian Inference ◽  
Force Field ◽  
Intrinsically Disordered Proteins ◽  
Probabilistic Method ◽  
Disordered Proteins ◽  
Saxs Data ◽  
Intrinsically Disordered ◽  
Protein Ensembles

A probabilistic method infers ensembles of intrinsically disordered proteins (IDPs) by combining SAXS data with a force field.

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 Molecular Dynamics Simulations of Phosphorylated Intrinsically Disordered Proteins: A Force Field Comparison

2021 ◽  
Vol 22 (18) ◽  
pp. 10174
Author(s):  
Ellen Rieloff ◽  
Marie Skepö
Keyword(s):  
Force Field ◽  
Intrinsically Disordered Proteins ◽  
Disordered Proteins ◽  
Conformational Ensemble ◽  
Salt Bridges ◽  
Post Translational Modification ◽  
Intrinsically Disordered ◽  
The Difference ◽  
Disordered Peptides ◽  
Dynamics Simulations

Phosphorylation is a common post-translational modification among intrinsically disordered proteins and regions, which helps regulate function by changing the protein conformations, dynamics, and interactions with binding partners. To fully comprehend the effects of phosphorylation, computer simulations are a helpful tool, although they are dependent on the accuracy of the force field used. Here, we compared the conformational ensembles produced by Amber ff99SB-ILDN+TIP4P-D and CHARMM36m, for four phosphorylated disordered peptides ranging in length from 14–43 residues. CHARMM36m consistently produced more compact conformations with a higher content of bends, mainly due to more stable salt bridges. Based on comparisons with experimental size estimates for the shortest and longest peptide, CHARMM36m appeared to overestimate the compactness. The difference between the force fields was largest for the peptide showing the greatest separation between positively charged and phosphorylated residues, in line with the importance of charge distribution. For this peptide, the conformational ensemble did not change significantly upon increasing the ionic strength from 0 mM to 150 mM, despite a reduction of the salt-bridging probability in the CHARMM36m simulations, implying that salt concentration has negligible effects in this study.

scholarly journals Integrating multiple experimental data to determine conformational ensembles of an intrinsically disordered protein

2020 ◽  
Author(s):  
Gregory-Neal W. Gomes ◽  
Mickaël Krzeminski ◽  
Ashley Namini ◽  
Erik. W. Martin ◽  
Tanja Mittag ◽  
...  
Keyword(s):  
Experimental Data ◽  
Single Molecule ◽  
Intrinsically Disordered Proteins ◽  
Resonance Energy Transfer ◽  
Resonance Energy ◽  
Intrinsically Disordered Protein ◽  
Disordered Proteins ◽  
Saxs Data ◽  
Conformational Ensembles ◽  
Intrinsically Disordered

AbstractIntrinsically disordered proteins (IDPs) have fluctuating heterogeneous conformations, which makes structural characterization challenging, but of great interest, since their conformational ensembles are the link between their sequences and functions. An accurate description of IDP conformational ensembles depends crucially on the amount and quality of the experimental data, how it is integrated, and if it supports a consistent structural picture. We have used an integrative modelling approach to understand how conformational restraints imposed by the most common structural techniques for IDPs: Nuclear Magnetic Resonance (NMR) spectroscopy, Small-angle X-ray Scattering (SAXS), and single-molecule Förster Resonance Energy Transfer (smFRET) reach concordance on structural ensembles for Sic1 and phosphorylated Sic1 (pSic1). To resolve apparent discrepancies between smFRET and SAXS, we integrated SAXS data with non-smFRET (NMR) data and reserved the new smFRET data for Sic1 and pSic1 as an independent validation. The consistency of the SAXS/NMR restrained ensembles with smFRET, which was not guaranteed a priori, indicates that the perturbative effects of NMR or smFRET labels on the Sic1 and pSic1 ensembles are minimal. Furthermore, the mutual agreement with such a diverse set of experimental data suggest that details of the generated ensembles can now be examined with a high degree of confidence to reveal distinguishing features of Sic1 vs. pSic1. From the experimentally well supported ensembles, we find they are consistent with independent biophysical models of Sic1’s ultrasensitive binding to its partner Cdc4. Our results underscore the importance of integrative modelling in calculating and drawing biological conclusions from IDP conformational ensembles.

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.

scholarly journals Configurational Entropy of Folded Proteins and Its Importance for Intrinsically Disordered Proteins

2021 ◽  
Vol 22 (7) ◽  
pp. 3420
Author(s):  
Meili Liu ◽  
Akshaya K. Das ◽  
James Lincoff ◽  
Sukanya Sasmal ◽  
Sara Y. Cheng ◽  
...  
Keyword(s):  
Force Field ◽  
Intrinsically Disordered Proteins ◽  
Force Fields ◽  
Configurational Entropy ◽  
Globular Proteins ◽  
Disordered Proteins ◽  
Radius Of Gyration ◽  
Body Protein ◽  
Field Development ◽  
Intrinsically Disordered

Many pairwise additive force fields are in active use for intrinsically disordered proteins (IDPs) and regions (IDRs), some of which modify energetic terms to improve the description of IDPs/IDRs but are largely in disagreement with solution experiments for the disordered states. This work considers a new direction—the connection to configurational entropy—and how it might change the nature of our understanding of protein force field development to equally well encompass globular proteins, IDRs/IDPs, and disorder-to-order transitions. We have evaluated representative pairwise and many-body protein and water force fields against experimental data on representative IDPs and IDRs, a peptide that undergoes a disorder-to-order transition, for seven globular proteins ranging in size from 130 to 266 amino acids. We find that force fields with the largest statistical fluctuations consistent with the radius of gyration and universal Lindemann values for folded states simultaneously better describe IDPs and IDRs and disorder-to-order transitions. Hence, the crux of what a force field should exhibit to well describe IDRs/IDPs is not just the balance between protein and water energetics but the balance between energetic effects and configurational entropy of folded states of globular proteins.

Do Molecular Dynamics Force Fields Accurately Model Ramachandran Distributions of Amino Acid Residues in Water?

2022 ◽  
Author(s):  
Brian Andrews ◽  
Jose Guerra ◽  
Reinhard Schweitzer-Stenner ◽  
Brigita Urbanc
Keyword(s):  
Molecular Dynamics ◽  
Amino Acid ◽  
Force Field ◽  
Intrinsically Disordered Proteins ◽  
Force Fields ◽  
Disordered Proteins ◽  
Amino Acid Residues ◽  
Intrinsically Disordered

Molecular dynamics (MD) is a powerful tool for studying intrinsically disordered proteins, however, its reliability depends on the accuracy of the force field. We here assess Amber ff14SB, Amber ff14SB,...

scholarly journals Full structural ensembles of intrinsically disordered proteins from unbiased molecular dynamics simulations

2020 ◽  
Author(s):  
Utsab R. Shrestha ◽  
Jeremy C. Smith ◽  
Loukas Petridis
Keyword(s):  
Molecular Dynamics ◽  
Md Simulation ◽  
Intrinsically Disordered Proteins ◽  
Force Fields ◽  
Disordered Proteins ◽  
Hamiltonian Replica Exchange ◽  
Intrinsically Disordered ◽  
Angle Scattering ◽  
Structural Ensembles ◽  
Dynamics Simulations

ABSTRACTMolecular dynamics (MD) simulation is widely used to complement ensemble-averaged experiments of intrinsically disordered proteins (IDPs). However, MD often suffers from limitations of inaccuracy in the force fields and inadequate sampling. Here, we show that enhancing the sampling using Hamiltonian replica-exchange MD led to unbiased ensembles of unprecedented accuracy, reproducing small-angle scattering and NMR chemical shift experiments, for three IDPs of variable sequence properties using two recently optimized force fields. Surprisingly, we reveal that despite differences in their sequence, the inter-chain statistics of all three IDPs are similar for short contour lengths (< 10 residues).

Sign in / Sign up

Export Citation Format

Share Document