How well does molecular simulation reproduce environment-specific conformations of the intrinsically disordered peptides PLP, TP2 and ONEG?

Reid, Lauren; Guzzetti, Ileana; Svensson, Tor; Carlsson, A.; Su, Wu Chou; Leek, Tomas; Sydow, Lena von; Czechtizky, Werngard; Miljak, Marija; Verma, Chandra; Maria, Leonardo De; Essex, Jonathan W.

doi:10.1039/d1sc03496k

Cited by 10 publications

(10 citation statements)

References 87 publications

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“…Therefore we carried forward our analysis with a structure‐based balanced force‐field CHARMM36m 31 that generates structural, dynamics, and thermodynamic properties of a protein system with better accuracy. Moreover, CHARMM36m is an ideal force field for all‐atoms MD simulations because of its ability to show better correlation between the MD simulated and experimental data as well as reproduce the conformational transitions of solvent‐soluble as well as membrane peptides/proteins 86 . There are hundreds of available crystal structures of SARS‐CoV‐2 M PRO solved at different temperatures; however, they lack detailed comparative study of their molecular descriptions of the structure and its dynamics in aqueous solution.…”

Section: Resultsmentioning

confidence: 99%

“…Moreover, CHARMM36m is an ideal force field for all-atoms MD simulations because of its ability to show better correlation between the MD simulated and experimental data as well as reproduce the conformational transitions of solvent-soluble as well as membrane peptides/proteins. 86 There are hundreds of available crystal structures of SARS-CoV-2 M PRO solved at different temperatures; however, they lack detailed comparative study of their molecular descriptions of the structure and its dynamics in aqueous solution. The dependency of structures on temperature has been vividly studied by many researchers, to acquire a better structure that will be relevant for molecular docking studies.…”

Section: Dynamics Of Catalytic Site Residuesmentioning

confidence: 99%

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Structural insights into SARS‐CoV‐2 main protease conformational plasticity

Dehury

Mishra

2023

J of Cellular Biochemistry

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The spread of different severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) variants underscores the need for insights into the structural properties of its structural and non‐structural proteins. The highly conserved homo‐dimeric chymotrypsin‐like protease (3CL MPRO), belonging to the class of cysteine hydrolases, plays an indispensable role in processing viral polyproteins that are involved in viral replication and transcription. Studies have successfully demonstrated the role of MPRO as an attractive drug target for designing antiviral treatments because of its importance in the viral life cycle. Herein, we report the structural dynamics of six experimentally solved structures of MPRO (i.e., 6LU7, 6M03, 6WQF, 6Y2E, 6Y84, and 7BUY including both ligand‐free and ligand‐bound states) at different resolutions. We have employed a structure‐based balanced forcefield, CHARMM36m through state‐of‐the‐art all‐atoms molecular dynamics simulations at µ‐seconds scale at room temperature (303K) and pH 7.0 to explore their structure‐function relationship. The helical domain‐III responsible for dimerization mostly contributes to the altered conformational states and destabilization of MPRO. A keen observation of the high degree of flexibility in the P5 binding pocket adjoining domain II‐III highlights the reason for observation of conformational heterogeneity among the structural ensembles of MPRO. We also observe a differential dynamics of the catalytic pocket residues His41, Cys145, and Asp187, which may lead to catalytic impairment of the monomeric proteases. Among the highly populated conformational states of the six systems, 6LU7 and 7M03 forms the most stable and compact MPRO conformation with intact catalytic site and structural integrity. Altogether, our findings from this extensive study provides a benchmark to identify physiologically relevant structures of such promising drug targets for structure‐based drug design and discovery of potent drug‐like compounds having clinical potential.

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Section: Resultsmentioning

confidence: 99%

Section: Dynamics Of Catalytic Site Residuesmentioning

confidence: 99%

Structural insights into SARS‐CoV‐2 main protease conformational plasticity

Dehury

Mishra

2023

J of Cellular Biochemistry

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“…In order to obtain the most probable low energy conformations and the conformational space of each CTD sequence, we applied PCA using Cartesian coordinates. PCA is a widely used dimensionality reduction method to represent high-dimensional conformational information into two-dimensional plots to visualize the conformational space that the simulations sampled. ,– ,– PCA of conformations will also provide information about the convergence of the simulations as the energy landscapes should be connected in converged simulations. It is expected to observe a broad free energy landscape from the PCA of IDPs as they span large conformational ensembles compared to structured proteins.…”

Section: Resultsmentioning

confidence: 99%

Complex Conformational Space of the RNA Polymerase II C-Terminal Domain upon Phosphorylation

Amith,

Dutagaci

2023

J. Phys. Chem. B

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Intrinsically disordered proteins (IDPs) have been closely studied during the past decade due to their importance in many biological processes. The disordered nature of this group of proteins makes it difficult to observe its full span of the conformational space using either experimental or computational studies. In this article, we explored the conformational space of the C-terminal domain (CTD) of RNA polymerase II (Pol II), which is also an intrinsically disordered low complexity domain, using enhanced sampling methods. We provided a detailed conformational analysis of model systems of CTD with different lengths; first with the last 44 residues of the human CTD sequence and finally the CTD model with 2-heptapeptide repeating units. We then investigated the effects of phosphorylation on CTD conformations by performing simulations at different phosphorylated states. We obtained broad conformational spaces in nonphosphorylated CTD models, and phosphorylation has complex effects on the conformations of the CTD. These complex effects depend on the length of the CTD, spacing between the multiple phosphorylation sites, ion coordination, and interactions with the nearby residues.

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“…Moreover, several studies also point out that the ff14SB force field overestimates the helix formation due to the usage of globular protein structures in the parameterization. 39,59,60 On the other hand, ff14IDPSFF is relatively recent within the set of force fields that attempt to include the IDP flexibility by adding and optimizing the CMAP correction terms in the potential energy function of ff14SB. After studying short peptides and RNA-binding protein HIV-1 Rev, Duong et al 59 concluded that the ff14IDPSFF force field promotes random coil conformations and disordered secondary structures, which is consistent with experiments.…”

Section: Discussionmentioning

confidence: 99%

Molecular dynamics simulations of an α-synuclein NAC domain fragment with a ff14IDPSFF IDP-specific force field suggest β-sheet intermediate states of fibrillation

Privat

Madurga

Mas

et al. 2022

Phys. Chem. Chem. Phys.

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How well does molecular simulation reproduce environment-specific conformations of the intrinsically disordered peptides PLP, TP2 and ONEG?

Abstract: Understanding the conformational ensembles of intrinsically disordered proteins and peptides (IDPs) in their various biological environments is essential for understanding their mechanisms and functional roles in the proteome, leading to...

Cited by 10 publications

References 87 publications

Structural insights into SARS‐CoV‐2 main protease conformational plasticity

Structural insights into SARS‐CoV‐2 main protease conformational plasticity

Complex Conformational Space of the RNA Polymerase II C-Terminal Domain upon Phosphorylation

Molecular dynamics simulations of an α-synuclein NAC domain fragment with a ff14IDPSFF IDP-specific force field suggest β-sheet intermediate states of fibrillation

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