Interfacial Polar Interactions Affect Gramicidin Channel Kinetics

AbstractExcept remdesivir, no specific antivirals for SARS-CoV-2 infection are currently available. Here, we characterize two small-molecule-compounds, named GRL-1720 and 5h, containing an indoline and indole moiety, respectively, which target the SARS-CoV-2 main protease (Mpro). We use VeroE6 cell-based assays with RNA-qPCR, cytopathic assays, and immunocytochemistry and show both compounds to block the infectivity of SARS-CoV-2 with EC50 values of 15 ± 4 and 4.2 ± 0.7 μM for GRL-1720 and 5h, respectively. Remdesivir permitted viral breakthrough at high concentrations; however, compound 5h completely blocks SARS-CoV-2 infection in vitro without viral breakthrough or detectable cytotoxicity. Combination of 5h and remdesivir exhibits synergism against SARS-CoV-2. Additional X-ray structural analysis show that 5h forms a covalent bond with Mpro and makes polar interactions with multiple active site amino acid residues. The present data suggest that 5h might serve as a lead Mpro inhibitor for the development of therapeutics for SARS-CoV-2 infection.

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Structural design principles for specific ultra-high affinity interactions between colicins/pyocins and immunity proteins

Scientific Reports ◽

10.1038/s41598-021-83265-2 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Avital Shushan ◽

Mickey Kosloff

Keyword(s):

Protein Interactions ◽

Structural Elements ◽

Protein Protein Interactions ◽

Immunity Protein ◽

Rational Engineering ◽

High Affinity ◽

Comparative Structure ◽

Polar Interactions ◽

Exquisite Specificity

AbstractThe interactions of the antibiotic proteins colicins/pyocins with immunity proteins is a seminal model system for studying protein–protein interactions and specificity. Yet, a precise and quantitative determination of which structural elements and residues determine their binding affinity and specificity is still lacking. Here, we used comparative structure-based energy calculations to map residues that substantially contribute to interactions across native and engineered complexes of colicins/pyocins and immunity proteins. We show that the immunity protein α1–α2 motif is a unique structurally-dissimilar element that restricts interaction specificity towards all colicins/pyocins, in both engineered and native complexes. This motif combines with a diverse and extensive array of electrostatic/polar interactions that enable the exquisite specificity that characterizes these interactions while achieving ultra-high affinity. Surprisingly, the divergence of these contributing colicin residues is reciprocal to residue conservation in immunity proteins. The structurally-dissimilar immunity protein α1–α2 motif is recognized by divergent colicins similarly, while the conserved immunity protein α3 helix interacts with diverse colicin residues. Electrostatics thus plays a key role in setting interaction specificity across all colicins and immunity proteins. Our analysis and resulting residue-level maps illuminate the molecular basis for these protein–protein interactions, with implications for drug development and rational engineering of these interfaces.

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Quantum–Classical Path Integral Simulation of Excess Proton Dynamics in a Water Dimer Embedded in the Gramicidin Channel

Journal of Chemical Theory and Computation ◽

10.1021/acs.jctc.0c01012 ◽

2021 ◽

Vol 17 (2) ◽

pp. 627-638

Author(s):

Marco Nava ◽

Nancy Makri

Keyword(s):

Path Integral ◽

Water Dimer ◽

Gramicidin Channel ◽

Classical Path ◽

Proton Dynamics

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Memory in Ion Channel Kinetics

Acta Biotheoretica ◽

10.1007/s10441-021-09415-1 ◽

2021 ◽

Author(s):

M. P. Silva ◽

C. G. Rodrigues ◽

W. A. Varanda ◽

R. A. Nogueira

Keyword(s):

Ion Channel ◽

Channel Kinetics ◽

Ion Channel Kinetics

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Arguments in favor of an aggregational model of the gramicidin channel: a reply

Biophysical Journal ◽

10.1016/s0006-3495(92)81862-3 ◽

1992 ◽

Vol 61 (2) ◽

pp. 588-589 ◽

Cited By ~ 1

Author(s):

G. Stark

Keyword(s):

Gramicidin Channel

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Role of Tryptophan Residues in Gramicidin Channel Organization and Function

Biophysical Journal ◽

10.1529/biophysj.107.124206 ◽

2008 ◽

Vol 95 (1) ◽

pp. 166-175 ◽

Cited By ~ 29

Author(s):

Amitabha Chattopadhyay ◽

Satinder S. Rawat ◽

Denise V. Greathouse ◽

Devaki A. Kelkar ◽

Roger E. Koeppe

Keyword(s):

Gramicidin Channel ◽

Tryptophan Residues ◽

And Function

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MODELING OF WOLFF–PARKINSON–WHITE SYNDROME

International Journal of Bifurcation and Chaos ◽

10.1142/s0218127403008922 ◽

2003 ◽

Vol 13 (12) ◽

pp. 3827-3834

Author(s):

ROBERT HINCH

Keyword(s):

Asymptotic Analysis ◽

Ion Channel ◽

Sodium Channel ◽

Channel Model ◽

Accessory Pathway ◽

Simplified Model ◽

Channel Kinetics ◽

White Syndrome ◽

Channel Density ◽

Wolff Parkinson White Syndrome

Wolff–Parkinson–White syndrome is a disease where an arrhythmia is caused by the ventricles being electrically excited by an additional accessory pathway that links the atria to the ventricles. The spread of the activation wave from this pathway to the ventricles is modeled using a simplified model of Hodgkin–Huxley sodium channel kinetics, in a two ion-channel model. The model is investigated both analytically (using an asymptotic analysis) and numerically, and both methods are shown to give the same result. It is found that for a given width of the accessory pathway, there is a critical sodium channel density needed for the activation wave to spread from the pathway to the tissue. This result provides an explanation for the success of class-I anti-arrhythmic drugs in treating Wolff–Parkinson–White syndrome.

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