<i>ff14IDPs</i> force field improving the conformation sampling of intrinsically disordered proteins

Dong, Song; Wang, Wei; Ye, Wei; Ji, Dingjue; Luo, Ray; Chen, Haifeng

doi:10.1111/cbdd.12832

Cited by 73 publications

(89 citation statements)

References 55 publications

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“…4). Such PMFs have been used to characterize the propensity for IDPs to assume specific ensemble characteristics, including IDP compactness (52; 53). Each construct preferentially adopted smaller α -helical character than the 84% reflected in pCaN when bound to CaM.…”

Section: Resultsmentioning

confidence: 99%

Electrostatic control of calcineurin's intrinsically-disordered regulatory domain binding to calmodulin

Sun

Cook

Creamer

et al. 2018

Biochimica et Biophysica Acta (BBA) - General Subjects

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Calcineurin (CaN) is a serine/threonine phosphatase that regulates a variety of physiological and pathophysiological processes in mammalian tissue. The calcineurin (CaN) regulatory domain (RD) is responsible for regulating the enzyme's phosphatase activity, and is believed to be highly-disordered when inhibiting CaN, but undergoes a disorder-to-order transition upon diffusion-limited binding with the regulatory protein calmodulin (CaM). The prevalence of polar and charged amino acids in the regulatory domain (RD) suggests electrostatic interactions are involved in mediating calmodulin (CaM) binding, yet the lack of atomistic-resolution data for the bound complex has stymied efforts to probe how the RD sequence controls its conformational ensemble and long-range attractions contribute to target protein binding. In the present study, we investigated via computational modeling the extent to which electrostatics and structural disorder facilitate CaM/CaN association kinetics. Specifically, we examined several RD constructs that contain the CaM binding region (CAMBR) to characterize the roles of electrostatics versus conformational diversity in controlling diffusion-limited association rates, via microsecond-scale molecular dynamics (MD) and Brownian dynamic (BD) simulations. Our results indicate that the RD amino acid composition and sequence length influence both the dynamic availability of conformations amenable to CaM binding, as well as long-range electrostatic interactions to steer association. These findings provide intriguing insight into the interplay between conformational diversity and electrostatically-driven protein-protein association involving CaN, which are likely to extend to wide-ranging diffusion-limited processes regulated by intrinsically-disordered proteins.

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Section: Resultsmentioning

confidence: 99%

Electrostatic control of calcineurin's intrinsically-disordered regulatory domain binding to calmodulin

Sun

Cook

Creamer

et al. 2018

Biochimica et Biophysica Acta (BBA) - General Subjects

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“…35, 36 The optimization of the CMAP correction terms for IDPs is described in detail in our previous works. 10–12 Root mean square deviations of population (termed RMS p ) among all bins were calculated to quantitatively measure the difference between MD and database populations and calculated with the equation 1. Briefly, the CMAP parameters were optimized iteratively until the MD distributions match the benchmark distributions within a given tolerance, set to be less than 0.10%.…”

Section: Methodsmentioning

confidence: 99%

“…Based on this strategy, we developed two IDP-specific force fields with limited corrections on eight disorder-promoting residues only (A, G, P, R, Q, S, E, and K as reported in the literature 13–16 ), ff99IDPs and ff14IDPs , assisted with the CMAP method. 10–12 These IDP-specific force fields were shown to improve the structural distributions of IDPs significantly. However, our statistical analyses show that order-promoting residues are also quite common in IDPs and IDRs, but ff99IDPs and ff14IDPs do not correct these residues.…”

Section: Introductionmentioning

confidence: 99%

“…Our previous analyses show that the lack of correction of these residues causes somewhat larger discrepancy with experiment on these residues even if overall improvement is apparent over the generic protein force fields. 10–12 We thus further hypothesized that it is beneficial to optimize the backbone dihedral terms for all 20 naturally occurring amino acids to improve the performance of an IDP-specific force field.…”

Section: Introductionmentioning

confidence: 99%

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The IDP-Specific Force Field ff14IDPSFF Improves the Conformer Sampling of Intrinsically Disordered Proteins

Dong

Luo

Chen

2017

J. Chem. Inf. Model.

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157

187

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Intrinsically disordered proteins (IDPs) or intrinsically disordered regions have not fixed tertiary structure, but play key roles in signal regulation, molecule recognition, and drug target. However it is difficult to study the structure and function of IDPs by traditional experimental methods because of their diverse conformations. Limitations of current generic protein force fields and solvent models were reported in the previous simulations of IDPs. We have also explored to overcome these limitations by developing ff99IDPs and ff14IDPs force fields to correct the dihedral distribution for eight disordered promoting residues often observed in IDPs and found encouraging improvements. Here, we extend our correction of backbone dihedral terms to all 20 naturally occurring amino acids in the IDP-specific force field (ff14IDPSFF) to further improve the quality in the modeling of IDPs. Extensive tests of seven IDPs and 14 unstructured short peptides show that the simulated Cα chemical shifts with the ff14IDPSFF force field are in quantitative agreement with those from NMR experiment and are more accurate than the base generic force field and also our previous ff14IDPs that only corrects the eight disorder-promoting amino acids. The influences of solvent models were also investigated and found to be less important. Finally our explicit solvent MD simulations further show that ff14IDPSFF can still be used to model structural and dynamical properties of two tested folded proteins, with a slightly better agreement in the loop regions for both structural and dynamical properties. These findings confirm that the newly developed IDP-specific force field ff14IDPSFF can improve the conformer sampling of intrinsically disordered proteins.

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“…19 In order to better reproduce the disordered conformation, a set of AMBER force fields ff99IDPs 20, 21 and others 22 were used, which were developed specially for IDPs with grid-based energy correction maps (CMAP) term 23, 24 to correct the dihedral of backbone for eight disordered-promotion residues of Alanine, Arginine, Glycine, Glutamine, Serine, Glutamic acid, Lysine, and Proline. By adding CMAP energy term, the Φ/Ψ distributions of the eight disorder-promoting residues have been improved with respect to the benchmark data of IDPs, while the root mean squared percentage deviation is less than 0.15% between the benchmark and the simulation 20 .…”

Section: Introductionmentioning

confidence: 99%

Conformation dynamics of the intrinsically disordered protein c-Myb with the ff99IDPs force field

et al. 2017

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The intrinsically disordered protein c-Myb plays a critical role in cellular proliferation and differentiation. Loss of c-myb function results in embryonic lethality due to failure of fetal hepatic hematopoiesis. The conformation dynamics of the intrinsically disordered c-Myb are still unknown. Here, molecular dynamics (MD) simulations with the intrinsically disordered protein force field ff99IDPs were used to study the conformation dynamics. In comparison with ff99SBildn, ff99IDPs can reproduce more diverse disordered conformers of c-Myb. The predicted secondary chemical shift under ff99IDPs is more close to that of experiment data than that under ff99SBildn. Therefore, ff99IDPs can sample native molten globule, native pre-molten globule and native coil conformers for c-Myb. These results are consistent with those of other intrinsically disordered proteins. Kinetic analysis of MD simulations shows that c-Myb folds via a two-state process and indicates that c-Myb folds in the order of tertiary folding and helical folding. The folding nucleus of KEL plays an essential role in stabilizing the folding state with dynamic correlation networks. The influences of solvent models for TIP3P, TIP4P-EW and TIP5P were also investigated and it was found that TIP3P and ff99IDPs are the best combination to research the conformer sampling of c-Myb. These results reveal the conformation dynamics of c-Myb and confirm that the ff99IDPs force field can be used to research the relationship between structure and function of other intrinsically disordered proteins.

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ff14IDPs force field improving the conformation sampling of intrinsically disordered proteins

Cited by 73 publications

References 55 publications

Electrostatic control of calcineurin's intrinsically-disordered regulatory domain binding to calmodulin

Electrostatic control of calcineurin's intrinsically-disordered regulatory domain binding to calmodulin

The IDP-Specific Force Field ff14IDPSFF Improves the Conformer Sampling of Intrinsically Disordered Proteins

Conformation dynamics of the intrinsically disordered protein c-Myb with the ff99IDPs force field

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