scholarly journals Unique properties of Zika NS2B-NS3pro complexes as decoded by experiments and MD simulations

2016 ◽  
Author(s):  
Amrita Roy ◽  
Liangzhong Lim ◽  
Shagun Srivastava ◽  
Jianxing Song
Keyword(s):  
Sequence Variation ◽  
Md Simulations ◽  
World Population ◽  
Nmr Studies ◽  
Allosteric Inhibitors ◽  
Open Conformation ◽  
C Terminus ◽  
Β Sheet ◽  
Insight Into ◽  
Close Contacts

ABSTRACTZika virus can be passed from a pregnant woman to her fetus, thus leading to birth defects including more than microcephaly. It has been recently estimated that one-third of the world population will be infected by Zika, but unfortunately no vaccine or medicine is available so far. Zika NS2B-NS3pro is essential for its replication and thus represents an attractive target for drug discovery/design. Here we characterized conformation, catalysis, inhibition and dynamics of linked and unlinked Zika NS2B-NS3pro complexes by both experiments and MD simulations. The results unveil the unique properties of Zika NS2B-NS3pro which are very different from Dengue one. Particularly, CD and NMR studies indicate that unlike Dengue, the C-terminal region of Zika NS2B with a significant sequence variation is highly disordered in the open conformation. Indeed, MD simulations reveal that up to 100 ns, the Dengue NS2B C-terminus constantly has close contacts with its NS3pro domain. By a sharp contrast, the Zika NS2B C-terminus loses the contacts with its NS3pro domain after 10 ns, further forming a short β-sheet characteristic of the closed conformation at 30 ns. Furthermore, we found that a small molecule, previously identified as an active site inhibitor for other flaviviral NS2B-NS3pro, inhibited Zika NS2B-NS3pro potently in an allosteric manner. Our study provides the first insight into the dynamics of Zika NS2B-NS3pro and further deciphers that it is susceptible to allosteric inhibition, which thus bears critical implications for the future development of therapeutic allosteric inhibitors.

scholarly journals Computational and NMR studies of RNA duplexes with an internal pseudouridine-adenosine base pair

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Indrajit Deb ◽  
Łukasz Popenda ◽  
Joanna Sarzyńska ◽  
Magdalena Małgowska ◽  
Ansuman Lahiri ◽  
...  
Keyword(s):  
Thermodynamic Stability ◽  
Base Pair ◽  
Nearest Neighbor ◽  
Md Simulations ◽  
Nmr Studies ◽  
Sequence Context ◽  
Sequence Dependence ◽  
Structural Context ◽  
Rna Duplexes ◽  
Insight Into

Abstract Pseudouridine (Ψ) is the most common chemical modification present in RNA. In general, Ψ increases the thermodynamic stability of RNA. However, the degree of stabilization depends on the sequence and structural context. To explain experimentally observed sequence dependence of the effect of Ψ on the thermodynamic stability of RNA duplexes, we investigated the structure, dynamics and hydration of RNA duplexes with an internal Ψ-A base pair in different nearest-neighbor sequence contexts. The structures of two RNA duplexes containing 5′-GΨC/3′-CAG and 5′-CΨG/3′-GAC motifs were determined using NMR spectroscopy. To gain insight into the effect of Ψ on duplex dynamics and hydration, we performed molecular dynamics (MD) simulations of RNA duplexes with 5′-GΨC/3′-CAG, 5′-CΨG/3′-GAC, 5′-AΨU/3′-UAA and 5′-UΨA/3′-AAU motifs and their unmodified counterparts. Our results showed a subtle impact from Ψ modification on the structure and dynamics of the RNA duplexes studied. The MD simulations confirmed the change in hydration pattern when U is replaced with Ψ. Quantum chemical calculations showed that the replacement of U with Ψ affected the intrinsic stacking energies at the base pair steps depending on the sequence context. The calculated intrinsic stacking energies help to explain the experimentally observed sequence dependent changes in the duplex stability from Ψ modification.

scholarly journals Effect of Protein Conformation and AMP Protonation State on Fireflies’ Bioluminescent Emission

Molecules ◽  
2019 ◽  
Vol 24 (8) ◽  
pp. 1565 ◽  
Author(s):  
Cristina Garcia-Iriepa ◽  
Isabelle Navizet
Keyword(s):  
Protein Conformation ◽  
Emission Spectra ◽  
Blue Shift ◽  
Md Simulations ◽  
Water Molecules ◽  
Protein Conformations ◽  
Protonation State ◽  
Open Conformation ◽  
Protein Environment ◽  
Insight Into

The emitted color in fireflies’ bioluminescent systems depends on the beetle species the system is extracted from and on different external factors (pH, temperature…) among others. Controlling the energy of the emitted light (i.e., color) is of crucial interest for the use of such bioluminescent systems. For instance, in the biomedical field, red emitted light is desirable because of its larger tissue penetration and lower energies. In order to investigate the influence of the protein environment and the AMP protonation state on the emitted color, the emission spectra of the phenolate-keto and phenolate-enol oxyluciferin forms have been simulated by means of MD simulations and QM/MM calculations, considering: two different protein conformations (with an open or closed C-terminal domain with respect to the N-terminal) and two protonation states of AMP. The results show that the emission spectra when considering the protein characterized by a closed conformation are blue-shifted compared to the open conformation. Moreover, the complete deprotonation of AMP phosphate group (AMP2−) can also lead to a blue-shift of the emission spectra but only when considering the closed protein conformation (open form is not sensitive to changes of AMP protonation state). These findings can be reasoned by the different interactions (hydrogen-bonds) found between oxyluciferin and the surrounding (protein, AMP and water molecules). This study gets partial insight into the possible origin of the emitted color modulation by changes of the pH or luciferase conformations.

scholarly journals The transient manifold structure of the p53 extreme C-terminal domain: insight into disorder, recognition, and binding promiscuity by molecular dynamics simulations

2017 ◽  
Vol 19 (32) ◽  
pp. 21287-21296 ◽  
Author(s):  
E. Fadda ◽  
M. G. Nixon
Keyword(s):  
Md Simulations ◽  
Binding Activity ◽  
Conformational Sampling ◽  
Stable Secondary Structure ◽  
Intrinsically Disordered ◽  
Dna Binding Activity ◽  
C Terminus ◽  
Dynamics Simulations ◽  
Tumour Suppressor P53 ◽  
Insight Into

The extreme C-terminus of the p53 tumour suppressor (p53-CTD) is a 30 residue long intrinsically disordered region, responsible for regulating the p53 DNA binding activity. Extensive conformational sampling through MD simulations of a p53-CTD derived peptide in solution highlights its propensity to form short and stable secondary structure motifs, specifically localized within the sequence.

scholarly journals Insight into the HIV-1 Vif SOCS-box–ElonginBC interaction

Open Biology ◽  
2013 ◽  
Vol 3 (11) ◽  
pp. 130100 ◽  
Author(s):  
Zhisheng Lu ◽  
Julien R. C. Bergeron ◽  
R. Andrew Atkinson ◽  
Torsten Schaller ◽  
Dennis A. Veselkov ◽  
...  
Keyword(s):  
Solution Structure ◽  
Hydrophobic Interactions ◽  
Dynamic Information ◽  
Ubiquitin Ligase Complex ◽  
Biophysical Studies ◽  
Viral Infectivity Factor ◽  
Β Sheet ◽  
Socs Box ◽  
Insight Into ◽  
Hiv 1

The HIV-1 viral infectivity factor (Vif) neutralizes cell-encoded antiviral APOBEC3 proteins by recruiting a cellular ElonginB (EloB)/ElonginC (EloC)/Cullin5-containing ubiquitin ligase complex, resulting in APOBEC3 ubiquitination and proteolysis. The suppressors-of-cytokine-signalling-like domain (SOCS-box) of HIV-1 Vif is essential for E3 ligase engagement, and contains a BC box as well as an unusual proline-rich motif. Here, we report the NMR solution structure of the Vif SOCS–ElonginBC (EloBC) complex. In contrast to SOCS-boxes described in other proteins, the HIV-1 Vif SOCS-box contains only one α-helical domain followed by a β-sheet fold. The SOCS-box of Vif binds primarily to EloC by hydrophobic interactions. The functionally essential proline-rich motif mediates a direct but weak interaction with residues 101–104 of EloB, inducing a conformational change from an unstructured state to a structured state. The structure of the complex and biophysical studies provide detailed insight into the function of Vif's proline-rich motif and reveal novel dynamic information on the Vif–EloBC interaction.

High-Field1H MAS and15N CP-MAS NMR Studies of Alanine Tripeptides and Oligomers:  Distinction of Antiparallel and Parallel β-Sheet Structures and Two Crystallographically Independent Molecules

2007 ◽  
Vol 111 (30) ◽  
pp. 9172-9178 ◽  
Author(s):  
Yu Suzuki ◽  
Michi Okonogi ◽  
Kazuo Yamauchi ◽  
Hiromichi Kurosu ◽  
Masataka Tansho ◽  
...  
Keyword(s):  
Mas Nmr ◽  
Nmr Studies ◽  
Independent Molecules ◽  
Cp Mas Nmr ◽  
Β Sheet

scholarly journals Insight into Inhibitor Binding in the Eukaryotic Proteasome: Computations of the 20S CP

2018 ◽  
Vol 19 (12) ◽  
pp. 3858
Author(s):  
Milan Hodošček ◽  
Nadia Elghobashi-Meinhardt
Keyword(s):  
Electrostatic Interactions ◽  
Active Sites ◽  
Sampling Period ◽  
Md Simulations ◽  
Structural Features ◽  
Relaxation Dynamics ◽  
Inhibitor Binding ◽  
Computational Analyses ◽  
Insight Into ◽  
Proteolytic Chamber

A combination of molecular dynamics (MD) simulations and computational analyses uncovers structural features that may influence substrate passage and exposure to the active sites within the proteolytic chamber of the 20S proteasome core particle (CP). MD simulations of the CP reveal relaxation dynamics in which the CP slowly contracts over the 54 ns sampling period. MD simulations of the SyringolinA (SylA) inhibitor within the proteolytic B 1 ring chamber of the CP indicate that favorable van der Waals and electrostatic interactions account for the predominant association of the inhibitor with the walls of the proteolytic chamber. The time scale required for the inhibitor to travel from the center of the proteolytic chamber to the chamber wall is on the order of 4 ns, accompanied by an average energetic stabilization of approximately −20 kcal/mol.

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