scholarly journals Intrinsically Disordered Energy Landscapes

2015 ◽  
Vol 5 (1) ◽  
Author(s):  
Yassmine Chebaro ◽  
Andrew J. Ballard ◽  
Debayan Chakraborty ◽  
David J. Wales
2021 ◽  
Author(s):  
Antonio B. Oliveira ◽  
Xingcheng Lin ◽  
Prakash Kulkarni ◽  
José N. Onuchic ◽  
Susmita Roy ◽  
...  

AbstractIntrinsically disordered proteins (IDPs) lack a rigid 3D structure and populate a polymorphic ensemble of conformations. Because of the lack of a reference conformation, their energy landscape representation in terms of reaction coordinates presents a daunting challenge. Here, our newly developed Energy Landscape Visualization Method (ELViM), a reaction coordinate-free approach, shows its prime application to explore frustrated energy landscapes of an intrinsically disordered protein, Prostate-Associated Gene 4 (PAGE4). PAGE4 is a transcriptional coactivator that potentiates the oncogene c-Jun. Two kinases, namely HIPK1 and CLK2, phosphorylate PAGE4 generating variants phosphorylated at different serine/threonine residues (HIPK1-PAGE4 and CLK2-PAGE4, respectively) with opposing functions. While HIPK1-PAGE4 predominantly phosphorylates Thr51 and potentiates c-Jun, CLK2-PAGE4 hyper-phosphorylates PAGE4 and attenuates transactivation. To understand the underlying mechanisms of conformational diversity among different phosphoforms, we have analyzed their atomistic trajectories simulated using AWSEM forcefield and the energy landscapes were elucidated using ELViM. This method allows us to identify and compare the population distributions of different conformational ensembles of PAGE4 phosphoforms using the same effective phase space. The results reveal a predominant conformational ensemble with an extended C-terminal segment of WT PAGE4, which exposes a functional residue Thr51, implying its potential of undertaking a fly-casting mechanism while binding to its cognate partner. In contrast, for HIPK1-PAGE4, a compact conformational ensemble enhances its population sequestering phosphorylated-Thr51. This clearly explains the experimentally observed weaker affinity of HIPK1-PAGE4 for c-Jun. ELViM appears as a powerful tool especially to analyze the highly-frustrated energy landscape representation of IDPs where appropriate reaction coordinates are hard to apprehend.


2019 ◽  
Vol 21 (10) ◽  
pp. 5634-5645 ◽  
Author(s):  
Xiakun Chu ◽  
Jin Wang

The topography of binding energy landscapes of intrinsically disordered proteins is hierarchically heterogeneous and modulated by the conformational disorder and salt concentration.


2019 ◽  
Vol 9 (7) ◽  
pp. 1498 ◽  
Author(s):  
Alberto Cappellaro ◽  
Luca Salasnich

We present a field-theory description of ultracold bosonic atoms in the presence of a disordered external potential. By means of functional integration techniques, we aim to investigate and review the interplay between disordered energy landscapes and fluctuations, both thermal and quantum ones. Within the broken-symmetry phase, up to the Gaussian level of approximation, the disorder contribution crucially modifies both the condensate depletion and the superfluid response. Remarkably, it is found that the ordered (i.e., superfluid) phase can be destroyed also in regimes where the random external potential is suitable for a perturbative analysis. We analyze the simplest case of quenched disorder and then we move to present the implementation of the replica trick for ultracold bosonic systems. In both cases, we discuss strengths and limitations of the reviewed approach, paying specific attention to possible extensions and the most recent experimental outputs.


2017 ◽  
Vol 13 (10) ◽  
pp. 2152-2159 ◽  
Author(s):  
Xu Shang ◽  
Wenting Chu ◽  
Xiakun Chu ◽  
Chuanbo Liu ◽  
Liufang Xu ◽  
...  

The intrinsically disordered protein (IDP) Chz.core, which is the interaction core of Chz1, shows binding preference to histone variant H2A.z. The coupled folding–binding mechanism of the complex can be quantified by the free energy landscapes.


2020 ◽  
Vol 22 (5) ◽  
pp. 2938-2948
Author(s):  
Ke Wang ◽  
Shangbo Ning ◽  
Yue Guo ◽  
Mojie Duan ◽  
Minghui Yang

The free energy landscapes of 4E-BP2 and its variants were obtained by replica-exchanged molecular dynamics, which elucidate the regulation mechanism of phosphorylation and mutations on the intrinsically disordered protein.


2020 ◽  
Author(s):  
Rajeswari Appadurai ◽  
Jayashree Nagesh ◽  
Anand Srivastava

AbstractDetermining the conformational ensemble for proteins with multi-funneled complex free-energy landscapes is often not possible with classical structure-biology methods that produce time and ensemble averaged data. With vastly improved force fields and advances in rare-event sampling methods, molecular dynamics (MD) simulations offer a complementary approach towards determining the collection of 3-dimensional structures that proteins can adopt. However, in general, MD simulations need to either impose restraints or reweigh the generated data to match experiments. The limitations extend beyond systems with high free-energy barriers as is the case with metamorphic proteins such as RFA-H. The predicted structures in even weakly-funneled intrinsically disordered proteins (IDPs) such as Histatin-5 (His-5) are too compact relative to experiments. Here, we employ a new computationally-efficient parallel-tempering based advanced-sampling method applicable across proteins with extremely diverse free-energy landscapes. And we show that the calculated ensemble averages match reasonably well with the NMR, SAXS and other biophysical experiments without the need to reweigh. We benchmark our method against standard model systems such as alanine di-peptide, TRP-cage and β-hairpin and demonstrate significant enhancement in the sampling efficiency. The method successfully scales to large metamorphic proteins such as RFA-H and to highly disordered IDPs such as His-5 and produces experimentally-consistent ensemble. By allowing accurate sampling across diverse landscapes, the method enables for ensemble conformational sampling of deep multi-funneled metamorphic proteins as well as highly flexible IDPs with shallow multi-funneled free-energy landscape.Significance/Authors’ SummaryGenerating high-resolution ensemble of intrinsically disordered proteins, particularly the highly flexible ones with high-charge and low-hydrophobicity and with shallow multi-funneled free-energy landscape, is a daunting task and often not possible since information from biophysical experiments provide time and ensemble average data at low resolutions. At the other end of the spectrum are the metamorphic proteins with multiple deep funnels and elucidating the structures of the transition intermediates between the fold topologies is a non-trivial exercise. In this work, we propose a new parallel-tempering based advanced-sampling method where the Hamiltonian is designed to allow faster decay of water orientation dynamics, which in turn facilitates accurate and efficient sampling across a wide variety of free-energy landscapes.


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