Molecular determinants of the modulation of the VSD-PD coupling mechanism of the KV7.1 channel by the KCNE1 ancillary subunits

H2O2 is a relatively long-lived reactive oxygen species that signals between cells and organisms. H2O2 signalling in plants is essential for response to stress, defence against pathogens and the regulation of programmed cell death. Although H2O2 diffusion across membranes is often considered as a passive property of lipid bilayers, native membranes represent significant barriers for H2O2. In the present study we addressed the question of whether channels might facilitate H2O2 conduction across plasma membranes. The expression of several plant plasma membrane aquaporins in yeast, including PIP2;1 from Arabidopsis (where PIP is plasma membrane intrinsic protein), enhanced the toxicity of H2O2 and increased the fluorescence of dye-loaded yeast when exposed to H2O2. The sensitivity of aquaporin-expressing yeast to H2O2 was altered by mutations that alter gating and the selectivity of the aquaporins. The conduction of water, H2O2 and urea was compared, using molecular dynamics simulations based on the crystal structure of SoPIP2;1 from spinach. The calculations identify differences in the conduction between the substrates and reveal channel residues critically involved in H2O2 conduction. The results of the calculations on tetramers and monomers are in agreement with the biochemical data. Taken together, the results strongly suggest that plasma membrane aquaporin pores determine the efficiency of H2O2 signalling between cells. Aquaporins are present in most species and their capacity to facilitate the diffusion of H2O2 may be of physiological significance in many organisms and particularly in communication between different species.

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Hierarchy of π-Stacking Determines the Conformational Preference of Bis-Squaraines

10.26434/chemrxiv.13041830.v1 ◽

2020 ◽

Author(s):

Abhishek Singh ◽

Reman K. Singh ◽

G Naresh Patwari

Keyword(s):

Hydrogen Bonding ◽

Rational Design ◽

Biological Molecules ◽

Conformational Space ◽

X Ray Crystallography ◽

Simple Strategy ◽

Induced Folding ◽

Π Stacking ◽

Varying Length ◽

Dynamics Simulations

The rational design of conformationally controlled foldable modules can lead to a deeper insight into the conformational space of complex biological molecules where non-covalent interactions such as hydrogen bonding and π-stacking are known to play a pivotal role. Squaramides are known to have excellent hydrogen bonding capabilities and hence, are ideal molecules for designing foldable modules that can mimic the secondary structures of bio-molecules. The π-stacking induced folding of bis-squaraines tethered using aliphatic primary and secondary-diamine linkers of varying length is explored with a simple strategy of invoking small perturbations involving the length linkers and degree of substitution. Solution phase NMR investigations in combination with molecular dynamics simulations suggest that bis-squaraines predominantly exist as extended conformations. Structures elucidated by X-ray crystallography confirmed a variety of folded and extended secondary conformations including hairpin turns and 𝛽-sheets which are determined by the hierarchy of π-stacking relative to N–H···O hydrogen bonds.

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Hierarchy of π-Stacking Determines the Conformational Preference of Bis-Squaraines

10.26434/chemrxiv.13041830 ◽

2020 ◽

Author(s):

Abhishek Singh ◽

Reman K. Singh ◽

G Naresh Patwari

Keyword(s):

Hydrogen Bonding ◽

Rational Design ◽

Biological Molecules ◽

Conformational Space ◽

X Ray Crystallography ◽

Simple Strategy ◽

Induced Folding ◽

Π Stacking ◽

Varying Length ◽

Dynamics Simulations

The rational design of conformationally controlled foldable modules can lead to a deeper insight into the conformational space of complex biological molecules where non-covalent interactions such as hydrogen bonding and π-stacking are known to play a pivotal role. Squaramides are known to have excellent hydrogen bonding capabilities and hence, are ideal molecules for designing foldable modules that can mimic the secondary structures of bio-molecules. The π-stacking induced folding of bis-squaraines tethered using aliphatic primary and secondary-diamine linkers of varying length is explored with a simple strategy of invoking small perturbations involving the length linkers and degree of substitution. Solution phase NMR investigations in combination with molecular dynamics simulations suggest that bis-squaraines predominantly exist as extended conformations. Structures elucidated by X-ray crystallography confirmed a variety of folded and extended secondary conformations including hairpin turns and 𝛽-sheets which are determined by the hierarchy of π-stacking relative to N–H···O hydrogen bonds.

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Faculty Opinions recommendation of Understanding the Hofmeister effect in interactions between chaotropic anions and lipid bilayers: molecular dynamics simulations.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1014605.194151 ◽

2003 ◽

Author(s):

Bradley Smith

Keyword(s):

Molecular Dynamics ◽

Molecular Dynamics Simulations ◽

Lipid Bilayers ◽

Hofmeister Effect ◽

Chaotropic Anions ◽

Dynamics Simulations

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Clustering and Sampling of the c-Met Conformational Space: A Computational Drug Discovery Study

Combinatorial Chemistry & High Throughput Screening ◽

10.2174/1386207322666191024103902 ◽

2020 ◽

Vol 22 (9) ◽

pp. 635-648 ◽

Cited By ~ 2

Author(s):

Korosh Mashayekh ◽

Shahrzad Sharifi ◽

Tahereh Damghani ◽

Maryam Elyasi ◽

Mohammad S. Avestan ◽

...

Keyword(s):

Critical Role ◽

Scientific Work ◽

Binding Mode ◽

Docking Studies ◽

Conformational Space ◽

Hydrogen Bond Interactions ◽

Docking Program ◽

Dynamics Simulations ◽

Computational Drug Discovery ◽

Dynamic Ensembles

Background: c-Met kinase plays a critical role in a myriad of human cancers, and a massive scientific work was devoted to design more potent inhibitors. Objective: In this study, 16 molecular dynamics simulations of different complexes of potent c-Met inhibitors with U-shaped binding mode were carried out regarding the dynamic ensembles to design novel potent inhibitors. Methods: A cluster analysis was performed, and the most representative frame of each complex was subjected to the structure-based pharmacophore screening. The GOLD docking program investigated the interaction energy and pattern of output hits from the virtual screening. The most promising hits with the highest scoring values that showed critical interactions with c-Met were presented for ADME/Tox analysis. Results: The screening yielded 45,324 hits that all of them were subjected to the docking studies and 10 of them with the highest-scoring values having diverse structures were presented for ADME/Tox analyses. Conclusion: The results indicated that all the hits shared critical Pi-Pi stacked and hydrogen bond interactions with Tyr1230 and Met1160 respectively.

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