Sampling Long- versus Short-Range Interactions Defines the Ability of Force Fields To Reproduce the Dynamics of Intrinsically Disordered Proteins

2017 ◽  
Vol 13 (9) ◽  
pp. 3964-3974 ◽  
Author(s):  
Davide Mercadante ◽  
Johannes A. Wagner ◽  
Iker V. Aramburu ◽  
Edward A. Lemke ◽  
Frauke Gräter
Keyword(s):  
Short Range ◽  
Intrinsically Disordered Proteins ◽  
Force Fields ◽  
Disordered Proteins ◽  
Intrinsically Disordered

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.

The accuracy of force fields on the simulation of intrinsically disordered proteins: A benchmark test on the human p53 tumor suppressor

2020 ◽  
Vol 19 (04) ◽  
pp. 2050011
Author(s):  
Shangbo Ning ◽  
Jun Liu ◽  
Na Liu ◽  
Dazhong Yan
Keyword(s):  
Md Simulation ◽  
Intrinsically Disordered Proteins ◽  
Force Fields ◽  
Chemical Shifts ◽  
Disordered Proteins ◽  
Experimental Measurements ◽  
Intrinsically Disordered ◽  
Structural Ensembles ◽  
Water Models ◽  
Structural Ensemble

Intrinsically disordered proteins (IDPs) are a class of proteins without stable three-dimensional structures under physiological conditions. IDPs exhibit high dynamic nature and could be described by structural ensembles. As one of the most widely used tools, molecular dynamics (MD) simulation could provide the atomic descriptions of the structural ensemble of IDPs. However, the accuracy of the MD simulation largely depends on the accuracy of the force field. In this paper, we compared the structural ensembles of the activation domain 1 (AD1) in p53 tumor suppressor obtained from the widely used force fields, AMBER99SB-ILDN, CHARMM27, CHARMM36m with different water models. The results show that CHARMM36m generates more extended conformations than other force fields, while CHARMM27 prefers to sample the [Formula: see text]-helical structure. Moreover, the chemical shifts obtained by CHARMM36m are the closest to the experimental measurements. These results indicate that the CHARMM36m force field performs best in characterizing the structure properties of p53 AD1. Water models are also critical to describe the structural ensemble of IDPs. TIP4P water model can obtain more extended conformations and produce more local helical conformations than the TIP3P model in our simulation. In addition, we also compare the chemical shifts predicted by different chemical shift predicting programs with experimental measurements, the results show that SHIFTX2 obtains the best performance in the chemical shifts prediction.

Comparison and Evaluation of Force Fields for Intrinsically Disordered Proteins

2020 ◽  
Vol 60 (10) ◽  
pp. 4912-4923 ◽  
Author(s):  
Mueed Ur Rahman ◽  
Ashfaq Ur Rehman ◽  
Hao Liu ◽  
Hai-Feng Chen
Keyword(s):  
Intrinsically Disordered Proteins ◽  
Force Fields ◽  
Disordered Proteins ◽  
Intrinsically Disordered

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 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.

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