Unraveling the folding-assisted unbinding mechanism of TCF with its binding partner ß-catenin.

This study utilizes molecular dynamics simulations aided with multiple walker parallel bias metadynamics to investigate the TCF unbinding mechanism from the ß-catenin interface. The results, consistent with experimental binding affinity calculations, unveil a folding-assisted unbinding mechanism.

Targeting RdRp of SARS-CoV-2 with De Novo Molecule Generation.

Viruses are known for their extremely high mutation rates, allowing them to evade both the human immune system and many forms of standard medicine. Despite this, the RNA dependent RNA polymerase (RdRp) of the RNA viruses has been largely conserved, and any significant mutation of this protein is unlikely. The recent COVID-19 pandemic presents a need for therapeutics. We have designed a de novo drug design algorithm that generates strong binding ligands from scratch, based on only the structure of the target protein's receptor. In this paper, we applied our method to target SARS-CoV-2 RdRp and generated several de novo molecules. We then chose some drug molecules based on the structural similarity to some of our strongest binding de novo molecules. Subsequently, we showed, using rigorous all-atom explicit-water free energy calculations in near-microsecond time scales using state-of-the-art well-tempered metadynamics simulations, that some of our de novo generated ligands bind more strongly to RdRp than the recent FDA approved drug remdesivir in its active form, remdesivir triphosphate (RTP). We elucidated the binding mechanism for some of the top binders and compared it with RTP. We believe that this work will be useful both by presenting lead structures for RdRp inhibition and by delivering key insights into the residues of the protein potentially involved in the binding/unbinding of these small molecule drugs, leading to more targeted studies in the future.

Molecular insights into the stereospecificity of arginine in RNA tetraloop folding.

One of the hypotheses for the homochirality of amino acids in the context of the origin of life is that only a particular stereoisomer provides preferential stability to RNA folding by acting as a chemical chaperon. However, the effect at the molecular level is not well understood. This study provides a molecular understanding of such preferential stability for a small GAAA RNA tetraloop in the presence of chiral arginine through a multidimensional free energy landscape constructed using a combination of umbrella sampling and parallel bias metadynamics (PBMetaD) simulations. We show that the origin of the chirality difference in RNA folding-unfolding dynamics is due to differences in the configurational diversity of RNA in adopting various non-natural conformations that accompany the diverse binding modes of D-arginine and L-arginine. We show that while D-arginine stabilizes the native folded state of RNA, L-arginine destabilizes it. Furthermore, free energy calculations on the binding of D- and L-arginine reveal a specific geometric constraint that helps D-arginine to stack with the terminal base pairs of RNA and pushes L-arginine for groove binding.

Self-assembled anion channel formation by bis(1,3-propanediol)-linked meta-dipropynylbenzene-based small molecules.

Two self-assembled barrel-rosette ion channels have been developed using bis(1,3-propanediol)-linked m-dipropynylbenzene-based molecules. The system with an additional amide arm acted as a better channel compared to that having an ester arm. The amide-linked channel displayed substantial channel activity and excellent chloride selectivity in the lipid bilayer membranes. Molecular dynamics simulation studies confirmed efficient hydrogen-bonded self-assembly of the amide-linked bis(1,3-propanediol)-based molecules in the lipid bilayer membrane and the detection of chloride recognition in the cavity.

Bis(cholyl)-based chloride channels with oxalamide and hydrazide selectivity filters.

We report the development of supramolecular bis(cholyl) ion channels using oxalamide and hydrazide as selectivity filters. The hydrazide system showed superior chloride transport activity to oxalamide via the formation of a barrel stave channel. The better chloride recognition within the hydrazide channel over the oxalalmide channel was confirmed from the theoretical calculations.

Atomistic De-novo Inhibitor Generation-Guided Drug Repurposing for SARS-CoV-2 Spike Protein with Free-Energy Validation by Well-Tempered Metadynamics.

Computational drug design is increasingly becoming important with new and unforeseen diseases like COVID-19. In this study, we present a new computational de novo drug design and repurposing method and applied it to find plausible drug candidates for the receptor binding domain (RBD) of SARS-CoV-2 (COVID-19). Our study comprises three steps: atom-by-atom generation of new molecules around a receptor, structural similarity mapping to existing approved and investigational drugs, and validation of their binding strengths to the viral spike proteins based on rigorous all-atom, explicit-water well-tempered metadynamics free energy calculations. By choosing the receptor binding domain of the viral spike protein, we showed that some of our new molecules and some of the repurposable drugs have stronger binding to RBD than hACE2. To validate our approach, we also calculated the free energy of hACE2 and RBD, and found it to be in an excellent agreement with experiments. These pool of drugs will allow strategic repurposing against COVID-19 for a particular prevailing conditions.

Apoptosis-inducing activity of a fluorescent barrel-rosette M+/Cl- channel.

Synthetic transmembrane ion transport systems are emerging as new tools for anticancer therapy. Here, a series of 2-hydroxy-N 1,N 3-diarylisophthalamide-based fluorescent ion channel-forming compounds are reported. Ion transport studies across large unilamellar vesicles confirmed that the compound with two 3,5-bis(trifluoromethyl)phenyl arms is the most efficient transporter among the series and it facilitates M+/Cl- symport. The compound formed supramolecular ion channels with a single-channel conductance of 100 ± 2 pS, a diameter of 5.06 ± 0.16 Å and a permeability ratio, P Cl- /P K+ , of 8.29 ± 1. The molecular dynamics simulations of the proposed M2.11 channel (i.e. 11 coaxial layers of a dimeric rosette) with K+ and Cl- in the preequilibrated POPC lipid bilayer with water molecules illustrated various aspects of channel formation and ion permeation. Cell viability assay with the designed compounds indicated that cell death is being induced by the individual compounds which follow the order of their ion transport activity and chloride and cations play roles in cell death. The inherent fluorescence of the most active transporter was helpful to monitor its permeation in cells by confocal microscopy. The apoptosis-inducing activity upon perturbation of intracellular ionic homeostasis was established by monitoring mitochondrial membrane depolarization, generation of reactive oxygen species, cytochrome c release, activation of the caspase 9 pathway, and finally the uptake of the propidium iodide dye in the treated MCF7 cells.