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.

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 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 Developing a molecular dynamics force field for both folded and disordered protein states

2018 ◽  
Vol 115 (21) ◽  
pp. E4758-E4766 ◽  
Author(s):  
Paul Robustelli ◽  
Stefano Piana ◽  
David E. Shaw
Keyword(s):  
Molecular Dynamics ◽  
Force Field ◽  
Md Simulation ◽  
State Of The Art ◽  
Force Fields ◽  
Md Simulations ◽  
Disordered Proteins ◽  
Disordered Protein ◽  
Data Points ◽  
Folded Proteins

Molecular dynamics (MD) simulation is a valuable tool for characterizing the structural dynamics of folded proteins and should be similarly applicable to disordered proteins and proteins with both folded and disordered regions. It has been unclear, however, whether any physical model (force field) used in MD simulations accurately describes both folded and disordered proteins. Here, we select a benchmark set of 21 systems, including folded and disordered proteins, simulate these systems with six state-of-the-art force fields, and compare the results to over 9,000 available experimental data points. We find that none of the tested force fields simultaneously provided accurate descriptions of folded proteins, of the dimensions of disordered proteins, and of the secondary structure propensities of disordered proteins. Guided by simulation results on a subset of our benchmark, however, we modified parameters of one force field, achieving excellent agreement with experiment for disordered proteins, while maintaining state-of-the-art accuracy for folded proteins. The resulting force field, a99SB-disp, should thus greatly expand the range of biological systems amenable to MD simulation. A similar approach could be taken to improve other force fields.

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 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.

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).

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