Biology subjects

Niklas, B.

Publications and source records attributed to Niklas, B..

4 recordsLinked to original sources

bioRxiv2025

Evaluating the ligands' potency to modulate the fast inactivation of voltage-gated sodium channel.

Electrical impulse transmission along the nerve fiber in the form of the action potential is possible due to fast conformational changes of voltage-gated sodium channels (Nav) that control the sodium ions flow into the cell. The transition between functional states, called the gating mechanism, can be modulated by natural toxins and drugs. Here, we propose to use steered molecular dynamics (SMD) to investigate the ability of various ligands to impact the gating of P. americana cockroach Nav. By calculating mechanical forces required to relocate the inactivation particle to its binding pocket or to dislocate it, we assessed ligands efficacy in trapping a channel in a given state (open or fast inactivated). Importantly, we showed that sulfonamide PF-05089771 and phospholipid PIP2 act as insect Nav channels inhibitors. We confirmed the ligands action by electrophysiological measurements of their ability to modulate the neural activity. Our approach, applied here on a cockroach channel, can be used in any other Nav, i.g, to evaluate new drug candidates.

biophysics↗

bioRxiv2025

multiSMD - a Python toolset for multidirectional Steered Molecular Dynamics

Understanding the direction-dependence of molecular interactions is critical for elucidating biological processes such as protein-protein binding, ligand dissociation, and mechanotransduction. While steered molecular dynamics (SMD) simulations enable the study of force-induced transitions, conventional single-direction approaches may overlook anisotropic responses inherent to biomolecular systems. Here, we present multiSMD, a Python-based tool that automates the setup and analysis of multi-directional SMD simulations in NAMD and GROMACS. By systematically probing forces along multiple spatial vectors, multiSMD captures direction-dependent phenomena--such as varying energy barriers or structural resilience--that remain hidden in traditional SMD. We demonstrate the utility of our approach through three distinct applications: (i) anisotropic unbinding in a protein-protein interaction, (ii) ligand dissociation pathways dependent on pulling direction, and (iii) force-induced remodeling of intrinsically disordered regions. multiSMD streamlines the exploration of mechanical anisotropy in biomolecules, offering a computational framework to guide experiments (e.g., AFM or optical tweezers) and uncover mechanistic insights inaccessible to single-axis methods. Availability and implementation: multiSMD is freely available at https://github.com/kszewc/multiSMD

bioinformatics↗

bioRxiv2025

Cytochrome P450 inhibition impedes pyrethroid effects on insects through Nav channel regulation

Insecticides used in various formulations are inevitable in agricultural pest control and prevention of vector-borne diseases. Piperonyl butoxide (PBO) is a synergist widely used to enhance the effectiveness of insecticides, notably pyrethroids, by inhibiting the detoxifying cytochrome P450 enzymes, thus reducing the capacity of insects to metabolize and resist insecticides. Recent studies, however, reveal an unexpectedly weak restoration of pyrethroid efficacy by PBO, but the underlying mechanism is unknown. Here, we demonstrate that the PBO-induced inhibition of cytochrome P450 impedes the effect of deltamethrin by mainly affecting its interaction with the inactivated state of voltage-gated sodium channels (Nav). We describe a new octopamine-dependent regulatory mechanism involving Gs, PKA, DARPP-32, and PP1-2A, which affect the cytochrome P450 conformation, thus limiting the effect of PBO and modulating the Nav gating. As a result, deltamethrin cannot reach its final binding site in the fenestration to exert its full effect. We confirmed in vivo that under chemical stressor, the level of octopamine is elevated, which decreases the deltamethrin efficacy. Our findings reveal a novel adaptation mechanism that increases insect survival by reducing insecticide efficacy, thus emphasizing the necessity of developing more effective formulations and technologies for pest and vector control.

pharmacology and toxicology↗

bioRxiv2023

Toward overcoming pyrethroid resistance in mosquito control: the role of sodium channel blocker insecticides

Diseases spread by mosquitoes lead to death of 700,000 people each year. The main way to reduce transmission is vector control by biting prevention with chemicals. However, the most commonly used insecticides lose efficacy due to the growing resistance. Voltage-gated sodium channels (VGSCs), membrane proteins responsible for the depolarizing phase of an action potential, are targeted by a broad range of neurotoxins, including pyrethroids and sodium channel blocker insecticides (SCBIs). Reduced sensitivity of the target protein due to the point mutations threatened malaria control with pyrethroids. Although SCBIs - indoxacarb (a pre-insecticide bioactivated to DCJW in insects) and metaflumizone - are used in agriculture only, they emerge as promising candidates in mosquito control. Therefore, a thorough understanding of molecular mechanisms of SCBIs action is urgently needed to break the resistance and stop disease transmission. In this study, by performing an extensive combination of equilibrium and enhanced sampling molecular dynamics simulations (3.2 s in total), we found the DIII-DIV fenestration to be the most probable entry route of DCJW to the central cavity of mosquito VGSC. Our study revealed that F1852 is crucial in limiting SCBI access to their binding site. Result explain the role of the F1852T mutation found in resistant insects and the increased toxicity of DCJW compared to its bulkier parent compound, indoxacarb. We also delineated residues that contribute to both SCBIs and non-ester pyrethroid etofenprox binding and thus could be involved in the target site cross-resistance. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=79 SRC="FIGDIR/small/534712v1_ufig1.gif" ALT="Figure 1"> View larger version (27K): org.highwire.dtl.DTLVardef@7912b1org.highwire.dtl.DTLVardef@ba624eorg.highwire.dtl.DTLVardef@8c28b3org.highwire.dtl.DTLVardef@1c42f3c_HPS_FORMAT_FIGEXP M_FIG C_FIG

biophysics↗