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Aedes aegypti (A. aegypti) is the principal vector for several diseases and despite having synthetic repellents to curb its feeding and transmission, they pose a threat to humans upon chronic use. Therefore, this study explores natural alternative thymol, via both structural and molecular binding properties against whole proteome targets of A. using a multi-target approach. Properties of thymol were studied using ProTox-II to determine the toxicity class. A preliminary screening of the proteome of A. aegypti was performed using existing microarray data analysis, conserved domain studies and protein modelling to narrow down the target categories. RaptorX standalone high-computing server was utilised for 309 protein structure modelling. Molecular docking was performed for 20 shortlisted protein categories against thymol, and top three docked complexes were simulated at 100 ns. Results showed that thymol belonged to class 4 low-toxicity, and molecular docking and 100 ns simulations in dynamic environment revealed stable complexes of thymol with glutathione-S-transferase (GST), octopamine receptor and glutamate-gated chloride channels (GGCC). Free energy binding via molecular mechanics revealed thymol with GST and GGCC to be stable. Our multi-target study presents insights into the molecular binding events that take place when thymol binds to newly identified A. aegypti targets. [ABSTRACT FROM AUTHOR]

In this paper, we review recent advances in the Continuous Fractional Component Monte Carlo (CFCMC) methodology and present a historic overview of the most important developments that have led to this method. The CFCMC method has gained attention for Monte Carlo simulations of adsorption at high loading, and phase and reaction equilibria of dense systems. It has recently been extended to reactive systems. The main features of the CFCMC method are: (1) Increased molecule exchange efficiency between different phases in single and multicomponent (reactive) systems, which improves the efficiency and accuracy of phase equilibria simulations at high densities; (2) Direct calculation of the chemical potential from a single simulation; (3) Direct calculation of partial molar properties from a single simulation. The developed simulation techniques are incorporated in the open-source molecular simulation software Brick-CFCMC. [ABSTRACT FROM AUTHOR]

A modified single sweep approach is proposed for generating free energy landscapes. The approach replaces the use of temperature-accelerated molecular dynamics (TAMD) to generate centres in collective variable (CV) space at which mean forces are computed using restrained molecular dynamics (MD) simulations with a sequential space-filling design. This approach also modifies the radial basis function reconstruction step of the traditional single sweep approach and proposes a weighted reconstruction of the free energy surface using the previously generated mean forces. The modified approach is compared to the traditional single sweep (SS) approach on the (φ, ψ) dihedral free-energy map of solvated alanine dipeptide (AD). It is found that the new approach results in a more accurate reconstructed free energy than does the traditional approach when compared to the directly-computed reference free energy landscape. It is shown that the increased accuracy of the overall map stems from the improved 1-dimensional space filling (projective) property of the proposed design compared to that of the TAMD generated centres. A further enhancement in the accuracy of the crucial lower energy regions is enabled by the introduction of weights in the reconstruction step that give more importance to lower energy-valued regions. [ABSTRACT FROM AUTHOR]

Free energies play a determining role in the transmembrane permeability of lipid bilayers to small molecules. The precision of the calculated free energies, in particular, can seriously affect the reliability of simulations of permeation events. Free energy profiles are evaluated with different known techniques for a water molecule inside a hydrated bilayer in order to assess the accuracy and precision of free energy calculations as well as the associated computational cost within the popular Groningen Machine for Chemical Simulations (GROMACS) software package. The different computational approaches employed include the method of constrained particles, umbrella sampling and thermodynamic integration. When free energy profiles computed from MD trajectories of similar timescales are compared, umbrella sampling is found to afford the best precision among the methods investigated, albeit at the expense of computational effort. [ABSTRACT FROM AUTHOR]

Fixed-charge force fields are a common choice for modelling solvents, many of which have been optimised around pure-component property predictions. Their use for modelling solvent mixtures, however, is questionable as the charge distribution of a molecule in the pure component and infinite dilution limits are expected to be different. Due to the small system sizes and simulation times typically used, it is not possible to observe phase-splitting in a molecular simulation. Here, we propose and demonstrate the efficient use of limiting activity coefficients computed using the conventional solvation free energy calculations in the infinite dilution and pure-component limits to evaluate whether or not the resulting solution is miscible. We demonstrate the application for binary aqueous systems with the following cosolvents: methanol, ethanol, 2-propanol, acetone and 1,4-dioxane. We find that the binary mixture of TIP4P water and TraPPE-UA 2-propanol is only partially miscible, as confirmed from detailed free energy analysis. One needs to take care when taking force fields off the shelf and applying them to model mixtures. The proposed strategy is general and not limited to molecular simulations with fixed-charge force fields, and we demonstrate its use with electronic structure calculations with the solvation model based on density continuum solvation model. [ABSTRACT FROM AUTHOR]

Formate channels play a crucial role in the metabolism of several different kinds of bacteria by bringing about uptake and export of formate ions. The current study investigates the structure, dynamics and ion channel activity of the formate channel FocA from Escherichia coli by employing extensive molecular dynamics (MD) simulations. The channel, known to be pH-sensitive, is modelled under different pH conditions by considering two different protonation states of a histidine residue. The results show that a fall in pH brings about an enhancement of the formate-conducting activity of the channel. The increased conductivity is a consequence of an overall widening of the pore at low pH, with the widening being brought about by movements of a pore-facing helical domain and a loop region. A fall in pH also enhances interactions between formate and the channel, leading to a lowering of the free energy barrier corresponding to formate transport. The findings provide detailed insights into how changes in pH can affect the shuttling of formate into and out of cells in physiologically important bacteria like enteric bacteria. [ABSTRACT FROM AUTHOR]