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

Guo, Xiaodong; Han, Jiaying; Luo, Ray; Chen, Haifeng

doi:10.1039/c7ra04133k

Cited by 17 publications

(14 citation statements)

References 43 publications

(30 reference statements)

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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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“…The results showed that the S2 region ensemble could adopt flexible and heterogeneous conformations, characteristic of an IDP. 3 Some force fields and implicit solvent models generate overestimation of compactness for the IDP ensembles, 52 , 53 and Figure 3 indicates that our simulations also show a modest increase in compaction compared to the predicted R g . However, chain compaction in IDPs depends on their sequences, for example, the fraction of charged residues and proline content.…”

Section: Resultsmentioning

confidence: 69%

Identification of an α-MoRF in the Intrinsically Disordered Region of the Escargot Transcription Factor

Hernández-Segura

Pastor

2020

ACS Omega

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Molecular recognition features (MoRFs) are common in intrinsically disordered proteins (IDPs) and intrinsically disordered regions (IDRs). MoRFs are in constant order–disorder structural transitions and adopt well-defined structures once they are bound to their targets. Here, we study Escargot (Esg), a transcription factor in Drosophila melanogaster that regulates multiple cellular functions, and consists of a disordered N-terminal domain and a group of zinc fingers at its C-terminal domain. We analyzed the N-terminal domain of Esg with disorder predictors and identified a region of 45 amino acids with high probability to form ordered structures, which we named S2. Through 54 μs of molecular dynamics (MD) simulations using CHARMM36 and implicit solvent (generalized Born/surface area (GBSA)), we characterized the conformational landscape of S2 and found an α-MoRF of ∼16 amino acids stabilized by key contacts within the helix. To test the importance of these contacts in the stability of the α-MoRF, we evaluated the effect of point mutations that would impair these interactions, running 24 μs of MD for each mutation. The mutations had mild effects on the MoRF, and in some cases, led to gain of residual structure through long-range contacts of the α-MoRF and the rest of the S2 region. As this could be an effect of the force field and solvent model we used, we benchmarked our simulation protocol by carrying out 32 μs of MD for the (AAQAA) 3 peptide. The results of the benchmark indicate that the global amount of helix in shorter peptides like (AAQAA) 3 is reasonably predicted. Careful analysis of the runs of S2 and its mutants suggests that the mutation to hydrophobic residues may have nucleated long-range hydrophobic and aromatic interactions that stabilize the MoRF. Finally, we have identified a set of residues that stabilize an α-MoRF in a region still without functional annotations in Esg.

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“…Besides, the cross‐correlation map, reflecting correlated motions between specific residues of proteins, was calculated using MD trajectories to probe the motion modes of MDM2. The cross‐correlation coefficient C ij of each pair C α atoms i and j , indicating the extent of correlated motion, were determined using the following equation

C_{ij} = \frac{< Δ r_{i} \cdot Δ r_{j} >}{{false(< normalΔ r_{i}^{2} > < normalΔ r_{j}^{2} > false)}^{1 false/ 2}}

in which Δ r i represents the displacement relative to the averaged position of the i th atom.…”

Section: Theory and Methodsmentioning

confidence: 99%

Inhibiting mechanism of small molecule toward the p53‐MDM2 interaction: A molecular dynamic exploration

et al. 2018

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Disruption of the p53-MDM2 interaction has been an efficient strategy to renew the function of wild-type p53. In this work, molecular dynamic simulations, molecular mechanics-generalized Born surface area method, and principal component analysis were combined to probe interaction mechanism of inhibitors 2TZ, 2U0, 2U1, 2U5, 2U6, and 2U7 with MDM2. The rank of our current predicted binding free energies is in agreement with that of the experimental values. The results demonstrate that the introductions of thiazole and pyridine rings into 2TZ as well as the change in the orientation of inhibitors lead to the increase in the polar interactions of 2U0, 2U1, 2U5, 2U6, and 2U7 with MDM2 relative to 2TZ. The information derived from principal component analysis suggests that inhibitor bindings produce significant effect on the binding cleft of MDM2 and make the binding cleft wider and bigger so as to accommodate different type inhibitors. This study is looked forward to contributing theoretical hints for designs of potent inhibitors targeting the p53-MDM2 interaction.

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

Cited by 17 publications

References 43 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

Identification of an α-MoRF in the Intrinsically Disordered Region of the Escargot Transcription Factor

Inhibiting mechanism of small molecule toward the p53‐MDM2 interaction: A molecular dynamic exploration

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