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).

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.

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 Characterization of partially ordered states in the intrinsically disordered N-terminal domain of p53 using millisecond molecular dynamics simulations

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Pablo Herrera-Nieto ◽  
Adrià Pérez ◽  
Gianni De Fabritiis
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulations ◽  
Intrinsically Disordered Proteins ◽  
Dynamical Behavior ◽  
Disordered Proteins ◽  
Partially Ordered ◽  
Intrinsically Disordered ◽  
State Models ◽  
Dynamics Simulations

Abstract The exploration of intrinsically disordered proteins in isolation is a crucial step to understand their complex dynamical behavior. In particular, the emergence of partially ordered states has not been explored in depth. The experimental characterization of such partially ordered states remains elusive due to their transient nature. Molecular dynamics mitigates this limitation thanks to its capability to explore biologically relevant timescales while retaining atomistic resolution. Here, millisecond unbiased molecular dynamics simulations were performed in the exemplar N-terminal region of p53. In combination with state-of-the-art Markov state models, simulations revealed the existence of several partially ordered states accounting for $$\sim $$ ∼ 40% of the equilibrium population. Some of the most relevant states feature helical conformations similar to the bound structure of p53 to Mdm2, as well as novel $$\beta $$ β -sheet elements. This highlights the potential complexity underlying the energy surface of intrinsically disordered proteins.

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