Metadynamics study of a β-hairpin stability in mixed solvents

Understanding the molecular mechanisms that allow some organisms to survive in extremely harsh conditions is an important achievement that might disclose a wide range of applications and that is constantly drawing the attention of many research fields. The high adaptability of these living creatures is related to the presence in their tissues of a high concentration of osmoprotectants, small organic, highly soluble molecules. Despite osmoprotectants having been known for a long time, a full disclosure of the machinery behind their activity is still lacking. Here we describe a computational approach that, taking advantage of the recently developed metadynamics technique, allows one to fully describe the free energy surface of a small β-hairpin peptide and how it is affected by an osmoprotectant, glycine betaine (GB) and for comparison by urea, a common denaturant. Simulations led to relevant thermodynamic information, including how the free energy difference of denaturation is affected by the two cosolvents; unlike urea, GB caused a considerable increase of the folded basin stability, which transposes into a higher melting temperature. NMR experiments confirmed the picture derived from the theoretical study. Further molecular dynamics simulations of selected conformations allowed investigation into deeper detail the role of GB in folded state protection. Simulations of the protein in GB solutions clearly showed an excess of osmoprotectant in the solvent bulk, rather than in the protein domain, confirming the exclusion from the protein surface, but also highlighted interesting features on its interactions, opening to new scenarios besides the classic "indirect mechanism" hypothesis.     

Vinblastine perturbation of tubulin protofilament structure: a computational insight

Tubulin is a heterodimeric protein whose self assembly leads to the formation of protofilaments and of more complex structures called microtubules, key components of the cytoskeleton which have a fundamental role in the cell division process. Due to its biological function, tubulin is the target of many antitumoral molecules that exert their action on proliferating tumoral cells. Among these drugs, vinblastine has been widely used in therapy for a long time, albeit its mechanism of interaction with tubulin has remained elusive until recently. Vinblastine acts as a microtubule destabilizing agent and induces the formation of curved or ring-shaped tubulin polymers instead of linear protofilaments in vitro. In this paper we compare, using molecular dynamics simulations and free energy calculations, the network of interactions that allow the assembly of model linear protofilaments with those present in curved tubulin polymers complexed with vinblastine. It is shown that vinblastine, wedging between tubulin heterodimers, actually mediates part of the interactions between them and acts by crosslinking the two proteins, leading to the observed curved polymers rather than to their disassembly.     

Structure-based virtual screening,in silico docking,ADME properties prediction and molecular dynamics studies for the identification of potential inhibitors against SARS-CoV-2 Mpro

COVID-19 is a viral pandemic caused by SARS-CoV-2. Due to its highly contagious nature, millions of people are getting affected worldwide knocking down the delicate global socio-economic equilibrium. According to the World Health Organization, COVID-19 has affected over 186 million people with a mortality of around 4 million as of July 09, 2021. Currently, there are few therapeutic options available for COVID-19 control. The rapid mutations in SARS-CoV-2 genome and development of new virulent strains with increased infection and mortality among COVID-19 patients, there is a great need to discover more potential drugs for SARS-CoV-2 on a priority basis. One of the key viral enzymes responsible for the replication and maturation of SARS-CoV-2 is M^pro protein. In the current study, structure-based virtual screening was used to identify four potential ligands against SARS-CoV-2 M^pro from a set of 8,722 ASINEX library compounds. These four compounds were evaluated using ADME filter to check their ADME profile and druggability, and all the four compounds were found to be within the current pharmacological acceptable range. They were individually docked to SARS-CoV-2 M^pro protein to assess their molecular interactions. Further, molecular dynamics (MD) simulations was carried out on protein–ligand complex using Desmond at 100 ns to explore their binding conformational stability. Based on RMSD, RMSF and hydrogen bond interactions, it was found that the stability of protein–ligand complex was maintained throughout the entire 100 ns simulations for all the four compounds. Some of the key ligand amino acid residues participated in stabilizing the protein–ligand interactions includes GLN 189, SER 10, GLU 166, ASN 142 with PHE 66 and TRP 132 of SARS-CoV-2 M^pro. Further optimization of these compounds could lead to promising drug candidates for SARS-CoV-2 M^pro target.

     

Halogen bonds with benzene: An assessment of DFT functionals

The performance of an extensive set of density functional theory functionals has been tested against CCSD(T) and MP2 results, extrapolated to the complete basis set (CBS) limit, for the interaction of either DCl or DBr (D = H, HCC, F, and NC) with the aromatic system of benzene. It was found that double hybrid functionals explicitly including dispersion, that is, B2PLYPD and mPW2PLYPD, provide the better agreement with the CCSD(T)/CBS results on both energies and equilibrium geometry, indicating the importance of dispersive contributions in determining this interaction. Among the less expensive functionals, the better performance is provided by the ωB97X and M062X functionals, while the ωB97XD and B97D functionals are shown to work very well for bromine complexes but not so well for chlorine complexes. © 2013 Wiley Periodicals, Inc.     

Total Synthesis and Biological Evaluation of Zealactone 1a/b

Strigolactones are plant hormones, which play pivotal roles in plant growth and development with potential application in sustainable agriculture. Recently, zealactone 1a/b has been identified as the major strigolactone from the root exudates of corn. Although zealactone is a promising molecule affecting signaling in the rhizosphere as well as in planta, evaluating its biological activities has been hampered by its low natural abundance and its relative chemical instability. Herein, we present the total synthesis of zealactone 1a/b based on our studies employing a [2+2]-cycloaddition strategy and a chemoselective Baeyer-Villiger oxidation to forge the γ-butyrolactone fragment. Furthermore, we disclose the biological activities of zealactone 1a/b on corn and in soil in comparison with related synthetic analogues.     

Halogen‐Bonding Interactions with π Systems: CCSD(T), MP2, and DFT Calculations

Halogen bonding is a noncovalent interaction between a halogen atom and a nucleophilic site. Interactions involving the π electrons of aromatic rings have received, up to now, little attention, despite the large number of systems in which they are present. We report binding energies of the interaction between either NCX or PhX (X=F, Cl, Br, I) and the aromatic benzene system as determined with the coupled cluster with perturbative triple excitations method [CCSD(T)] extrapolated at the complete basis set limit. Results are compared with those obtained by Møller–Plesset perturbation theory to second order (MP2) and density functional theory (DFT) calculations by using some of the most common functionals. Results show the important role of DFT in studying this interaction.     

Total Synthesis and Biological Evaluation of Heliolactone

Strigolactones are phytohormones, which affect diverse aspects of plant growth and development with potential application in modern agriculture. Recently, heliolactone has been isolated as a non‐canonical type of strigolactone from the root exudates of sunflower, and it could be involved in signaling in the rhizosphere as well as in planta. However, its biological activity is yet to be evaluated, due to its relative chemical instability and its low natural abundance. Herein, we describe the gram‐scale synthesis of heliolactone and its derivatives by using Stille cross‐coupling as the key bond‐forming reaction, and we disclose some of their biological activities (soil stability, binding ability to strigolactone receptor, corn germination, sunflower germination, Orobanche cumana germination and leaf senescence) in comparison with other canonical and non‐canonical strigolactones.     

Halogen bonding in ligand-receptor systems in the framework of classical force fields

Halogen bond is an important non-covalent interaction which is receiving a growing attention in the study of protein-ligand complexes. Many drugs are halogenated molecules and it has been recently shown that many halogenated ligands establish halogen bonds with biomolecules. As the halogen bond nature is due to an anisotropy of the electrostatic potential around halogen atoms, it is not possible to use traditional force fields based on a set of atom-centred charges to study halogen bonds in biomolecules. We show that the introduction of pseudo-atoms on halogens permits us to correctly describe the anisotropy of the electrostatic potential and to perform molecular dynamics simulations on complexes of proteins with halogenated ligands that reproduce experimental values. The results are compared with crystallographic data and with hybrid quantum mechanics/molecular mechanics calculations.     

Design,Synthesis and Biological Evaluation of Simplified Analogues of the Major Corn Strigolactones,Zealactone and Zeapyranolactone

Strigolactones are one of the phytohormones, which have multiple activities on plant growth and development. Since these strigolactone activities are highly associated with crop yield, use of strigolactone could be a promising technology in modern sustainable agriculture. The major strigolactones in corn root exudates have been identified as zealactone 1a/b and zeapyranolactone. We recently disclosed the first total synthesis of zealactone 1a/b together with its biological activity in corn. Herein, we describe the design and synthesis of simplified analogues of both corn-derived strigolactones with their bioavailability in soil and their biological activities. These compounds would be potential leads for the development of synthetic strigolactones for the agronomical use in a more sustainable crop production.     

Stereoselective Synthesis and Biological Profile of All Stereoisomers of Lactam Analogues of Strigolactones GR24 and GR18

Strigolactones (SLs) are signaling molecules involved in plant development and governing interactions with soil microorganisms in the rhizosphere as well as the germination of parasitic weeds. Developing their use in Crop Protection is a promising approach to a sustainable agriculture by mitigating biotic and abiotic stresses. Recently, a new class of lactam analogues of SL has emerged, namely strigolactams, displaying outstanding potency to induce the germination of parasitic weed O. cumana as well as enhanced chemical and soil stability. Herein, we describe the stereoselective synthesis of GR24 and GR18 lactams harnessing the chemistry of chiral keteniminium (KI) salts, in particular the unprecedented reactivity of chloro-substituted KI, supported by DFT calculations. We disclose subsequently the biological activity on corn of the 32 stereopure strigolactams prepared, highlighting the crucial influence of stereochemistry and lactam substitution, rationalized by docking analyses. Finally, we performed stability studies in soil, which reveal that stereoisomers display very different half-lives, reflecting the significant impact of stereochemistry on degradation kinetics.