Suppression of weed and insect populations by living and straw mulches in sesame (Sesamum indicum L.).

In order to evaluate the effect of different weed management treatments on weeds, pest and natural enemies populations in sesame (Sesamum indicum L.), a 2-year study was conducted in East Azarbaijan, Iran in 2020-2021. The study was conducted based on randomized complete block design with four replications. The weed management treatments consisted of trifluralin use (960 g ai ha-1), wheat straw mulch (WSM), living mulches of fenugreek (Trigonella foenum-graecum L.) (FLM), bitter vetch (Vicia ervilia L.) (VLM), calendula (Calendula officinalis L.) (CLM) and one-time hand weeding (OHW). The effect of weed management treatment was significant on densities of insect pests, natural enemies and weed and also weed biomass and sesame seed yield. The lowest densities of insect pests including Myzus persicae, Brevicoryne brassicae, Helicoverpa armigera and Spodoptera exigua were observed in CLM treatment. Also, the highest densities of natural enemies Coccinella septompunctata, Coccinella undecimpunctata and Orius niger were observed in CLM treatment. The highest reductions in grass (51.0%), broadleaf (72.0%), and total (62.6%) weed biomasses and highest seed yield (1456 kg ha-1) were obtained in OHW. The seed yields in CLM and WSM treatments were not significantly different with trifluralin treatment and could be recommended in sustainable production of sesame.

Taming multiple binding poses in alchemical binding free energy prediction: the ß-cyclodextrin host-guest SAMPL9 blinded challenge.

We apply the Alchemical Transfer Method (ATM) and a bespoke fixed partial charge force field to the SAMPL9 bCD host-guest binding free energy prediction challenge that comprises a combination of complexes formed between five phenothiazine guests and two cyclodextrin hosts. Multiple chemical forms, competing binding poses, and computational modeling challenges pose significant obstacles to obtaining reliable computational predictions for these systems. The phenothiazine guests exist in solution as racemic mixtures of enantiomers related by nitrogen inversions that bind the hosts in various binding poses, each requiring an individual free energy analysis. Due to the large size of the guests and the conformational reorganization of the hosts, which prevent a direct absolute binding free energy route, binding free energies are obtained by a series of absolute and relative binding alchemical steps for each chemical species in each binding pose. Metadynamics-accelerated conformational sampling was found to be necessary to address the poor convergence of some numerical estimates affected by conformational trapping. Despite these challenges, our blinded predictions quantitatively reproduced the experimental affinities for the ß-cyclodextrin host and, to a lesser extent, those with a methylated derivative. The work illustrates the challenges of obtaining reliable free energy data in in silico drug design for even seemingly simple systems and introduces some of the technologies available to tackle them.

Field and Laboratory Observations on the Biology of Aceria angustifoliae with Emphasis on Emergence of Overwintering Mites.

Data on the life strategy of A. angustifoliae (population fluctuation in buds and on leaves, emergence and migration to the overwintering sites), as well as its temperature-dependent emergence from overwintering sites at constant temperatures, were determined. The eriophyid mite overwintered into buds and the density of active mites inside them from winter 2017 to spring 2018 was higher than that in winter 2018-spring 2019. In the second half of March 2018 and in winter 2018-spring 2019, the mite density inside the buds decreased gradually with a peak of emergence occurring at the beginning of plant blossoming. Population density on leaves increased in summer, reaching a higher and later peak in 2018, and gradually decreased in autumn with mites migrating to overwintering sites. A lower developmental threshold of 4.5 °C was calculated. About half of the mite population was estimated to emerge from the overwintering sites at an accumulation of degree days ranging, on average, between 85.5 (at 20 °C) and 104.4 (at 10 °C) degree days above the assessed threshold.

Relative Binding Free Energy Calculations for Ligands with Diverse Scaffolds with the Alchemical Transfer Method.

We present an extension of the alchemical transfer method (ATM) for the estimation of relative binding free energies of molecular complexes applicable to conventional, as well as scaffold-hopping, alchemical transformations. Named ATM-RBFE, the method is implemented in the free and open-source OpenMM molecular simulation package and aims to provide a simpler and more generally applicable route to the calculation of relative binding free energies than what is currently available. ATM-RBFE is based on sound statistical mechanics theory and a novel coordinate perturbation scheme designed to swap the positions of a pair of ligands such that one is transferred from the bulk solvent to the receptor binding site while the other moves simultaneously in the opposite direction. The calculation is conducted directly in a single solvent box with a system prepared with conventional setup tools, without splitting of electrostatic and nonelectrostatic transformations, and without pairwise soft-core potentials. ATM-RBFE is validated here against the absolute binding free energies of the SAMPL8 GDCC host-guest benchmark set and against protein-ligand benchmark sets that include complexes of the estrogen receptor ERα and those of the methyltransferase EZH2. In each case the method yields self-consistent and converged relative binding free energy estimates in agreement with absolute binding free energies and reference literature values, as well as experimental measurements.

Application of the alchemical transfer and potential of mean force methods to the SAMPL8 host-guest blinded challenge.

We report the results of our participation in the SAMPL8 GDCC Blind Challenge for host-guest binding affinity predictions. Absolute binding affinity prediction is of central importance to the biophysics of molecular association and pharmaceutical discovery. The blinded SAMPL series have provided an important forum for assessing the reliability of binding free energy methods in an objective way. In this challenge, we employed two binding free energy methods, the newly developed alchemical transfer method (ATM) and the well-established potential of mean force (PMF) physical pathway method, using the same setup and force field model. The calculated binding free energies from the two methods are in excellent quantitative agreement. Importantly, the results from the two methods were also found to agree well with the experimental binding affinities released subsequently, with R values of 0.89 (ATM) and 0.83 (PMF). These results were ranked among the best of the SAMPL8 GDCC challenge and second only to those obtained with the more accurate AMOEBA force field. Interestingly, the two host molecules included in the challenge (TEMOA and TEETOA) displayed distinct binding mechanisms, with TEMOA undergoing a dehydration transition whereas guest binding to TEETOA resulted in the opening of the binding cavity that remains essentially dry during the process. The coupled reorganization and hydration equilibria observed in these systems is a useful prototype for the study of these phenomena often observed in the formation of protein-ligand complexes. Given that the two free energy methods employed here are based on entirely different thermodynamic pathways, the close agreement between the two and their general agreement with the experimental binding free energies are a testament to the high quality and precision achieved by theory and methods. The study provides further validation of the novel ATM binding free energy estimation protocol and paves the way to further extensions of the method to more complex systems.

Alchemical Transfer Approach to Absolute Binding Free Energy Estimation.

The alchemical transfer method (ATM) for the calculation of standard binding free energies of noncovalent molecular complexes is presented. The method is based on a coordinate displacement perturbation of the ligand between the receptor binding site and the explicit solvent bulk and a thermodynamic cycle connected by a symmetric intermediate in which the ligand interacts with the receptor and solvent environments with equal strength. While the approach is alchemical, the implementation of the ATM is as straightforward as that for physical pathway methods of binding. The method is applicable, in principle, with any force field, as it does not require splitting the alchemical transformations into electrostatic and nonelectrostatic steps, and it does not require soft-core pair potentials. We have implemented the ATM as a freely available and open-source plugin of the OpenMM molecular dynamics library. The method and its implementation are validated on the SAMPL6 SAMPLing host-guest benchmark set. The work paves the way to streamlined alchemical relative and absolute binding free energy implementations on many molecular simulation packages and with arbitrary energy functions including polarizable, quantum-mechanical, and artificial neural network potentials.

Alchemical transformations for concerted hydration free energy estimation with explicit solvation.

We present a family of alchemical perturbation potentials that enable the calculation of hydration free energies of small- to medium-sized molecules in a single concerted alchemical coupling step instead of the commonly used sequence of two distinct coupling steps for Lennard-Jones and electrostatic interactions. The perturbation potentials we employ are non-linear functions of the solute-solvent interaction energy designed to focus sampling near entropic bottlenecks along the alchemical pathway. We present a general framework to optimize the parameters of alchemical perturbation potentials of this kind. The optimization procedure is based on the λ-function formalism and the maximum-likelihood parameter estimation procedure we developed earlier to avoid the occurrence of multi-modal distributions of the coupling energy along the alchemical path. A novel soft-core function applied to the overall solute-solvent interaction energy rather than individual interatomic pair potentials critical for this result is also presented. Because it does not require modifications of core force and energy routines, the soft-core formulation can be easily deployed in molecular dynamics simulation codes. We illustrate the method by applying it to the estimation of the hydration free energy in water droplets of compounds of varying size and complexity. In each case, we show that convergence of the hydration free energy is achieved rapidly. This work paves the way for the ongoing development of more streamlined algorithms to estimate free energies of molecular binding with explicit solvation.