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

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.

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

10.1101/2020.06.16.155374 ◽

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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Using Chemical Shifts to Generate Structural Ensembles for Intrinsically Disordered Proteins with Converged Distributions of Secondary Structure

Biophysical Journal ◽

10.1016/j.bpj.2014.11.1256 ◽

2015 ◽

Vol 108 (2) ◽

pp. 227a-228a

Author(s):

F. Marty Ytreberg ◽

Wade Borcherds ◽

Hongwei Wu ◽

Gary W. Daughdrill

Keyword(s):

Secondary Structure ◽

Intrinsically Disordered Proteins ◽

Chemical Shifts ◽

Disordered Proteins ◽

Intrinsically Disordered ◽

Structural Ensembles

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Using chemical shifts to generate structural ensembles for intrinsically disordered proteins with converged distributions of secondary structure

Intrinsically Disordered Proteins ◽

10.4161/21690707.2014.984565 ◽

2015 ◽

Vol 3 (1) ◽

pp. e984565 ◽

Cited By ~ 6

Author(s):

F Marty Ytreberg ◽

Wade Borcherds ◽

Hongwei Wu ◽

Gary W Daughdrill

Keyword(s):

Secondary Structure ◽

Intrinsically Disordered Proteins ◽

Chemical Shifts ◽

Disordered Proteins ◽

Intrinsically Disordered ◽

Structural Ensembles

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

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1907251116 ◽

2019 ◽

Vol 116 (41) ◽

pp. 20446-20452 ◽

Cited By ~ 9

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.

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MD Simulation Trajectories of Multiple Intrinsically Disordered Proteins Reveal Order to Disorder Transitions that Bear Functional Significance

Biophysical Journal ◽

10.1016/j.bpj.2013.11.2733 ◽

2014 ◽

Vol 106 (2) ◽

pp. 484a

Author(s):

Tasneem Ali ◽

Mattaparthi Venkata ◽

Satish Kumar ◽

Saurabh Basu ◽

Rajaram Swaminathan

Keyword(s):

Functional Significance ◽

Md Simulation ◽

Intrinsically Disordered Proteins ◽

Disordered Proteins ◽

Intrinsically Disordered

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Higher Accuracy Achieved in the Simulations of Protein Structure Refinement, Protein Folding, and Intrinsically Disordered Proteins Using Polarizable Force Fields

The Journal of Physical Chemistry Letters ◽

10.1021/acs.jpclett.8b03471 ◽

2018 ◽

Vol 9 (24) ◽

pp. 7110-7116 ◽

Cited By ~ 7

Author(s):

Anhui Wang ◽

Zhichao Zhang ◽

Guohui Li

Keyword(s):

Protein Folding ◽

Protein Structure ◽

Intrinsically Disordered Proteins ◽

Force Fields ◽

Structure Refinement ◽

Disordered Proteins ◽

Polarizable Force Fields ◽

Intrinsically Disordered ◽

Protein Structure Refinement

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Faculty Opinions recommendation of Systematic Differences between Current Molecular Dynamics Force Fields To Represent Local Properties of Intrinsically Disordered Proteins.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.739366764.793582254 ◽

2021 ◽

Author(s):

Alex MacKerell

Keyword(s):

Molecular Dynamics ◽

Intrinsically Disordered Proteins ◽

Force Fields ◽

Disordered Proteins ◽

Intrinsically Disordered ◽

Local Properties

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Random coil chemical shifts for serine, threonine and tyrosine phosphorylation over a broad pH range

Journal of Biomolecular NMR ◽

10.1007/s10858-019-00283-z ◽

2019 ◽

Vol 73 (12) ◽

pp. 713-725 ◽

Cited By ~ 4

Author(s):

Ruth Hendus-Altenburger ◽

Catarina B. Fernandes ◽

Katrine Bugge ◽

Micha B. A. Kunze ◽

Wouter Boomsma ◽

...

Keyword(s):

Chemical Shift ◽

Secondary Structure ◽

Intrinsically Disordered Proteins ◽

Chemical Shifts ◽

Random Coil ◽

Disordered Proteins ◽

Phosphoryl Group ◽

Intrinsically Disordered ◽

Intrinsically Disordered Regions ◽

Secondary Chemical

Abstract Phosphorylation is one of the main regulators of cellular signaling typically occurring in flexible parts of folded proteins and in intrinsically disordered regions. It can have distinct effects on the chemical environment as well as on the structural properties near the modification site. Secondary chemical shift analysis is the main NMR method for detection of transiently formed secondary structure in intrinsically disordered proteins (IDPs) and the reliability of the analysis depends on an appropriate choice of random coil model. Random coil chemical shifts and sequence correction factors were previously determined for an Ac-QQXQQ-NH2-peptide series with X being any of the 20 common amino acids. However, a matching dataset on the phosphorylated states has so far only been incompletely determined or determined only at a single pH value. Here we extend the database by the addition of the random coil chemical shifts of the phosphorylated states of serine, threonine and tyrosine measured over a range of pH values covering the pKas of the phosphates and at several temperatures (www.bio.ku.dk/sbinlab/randomcoil). The combined results allow for accurate random coil chemical shift determination of phosphorylated regions at any pH and temperature, minimizing systematic biases of the secondary chemical shifts. Comparison of chemical shifts using random coil sets with and without inclusion of the phosphoryl group, revealed under/over estimations of helicity of up to 33%. The expanded set of random coil values will improve the reliability in detection and quantification of transient secondary structure in phosphorylation-modified IDPs.

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