Quantum simulations of SARS-CoV-2 main protease M enable high-quality scoring of diverse ligands.

The COVID-19 pandemic has led to unprecedented efforts to identify drugs that can reduce its associated morbidity/mortality rate. Computational chemistry approaches hold the potential for triaging potential candidates far more quickly than their experimental counterparts. These methods have been widely used to search for small molecules that can inhibit critical proteins involved in the SARS-CoV-2 replication cycle.

The Structural Basis for Low Conductance in the Membrane Protein VDAC upon β-NADH Binding and Voltage Gating.

The voltage-dependent anion channel (VDAC) forms the primary diffusion pore of the outer mitochondrial membrane. In its apo form, VDAC adopts an open conformation with high conductance. States of lower conductance can be induced by ligand binding or the application of voltage.

Physical Accuracy Leads to Biological Relevance: Best Practices For Simulating Ligand-Gated Ion Channels Interacting With General Anesthetics.

Efforts to detect binding modes of general anesthetics (GAs) for pentameric ligand-gated ion channels (pLGICs) are often complicated by a large number of indicated sites, as well as the challenges of ranking sites by affinity and determining which sites are occupied at clinical concentrations. Physics-based computational methods offer a powerful route for determining affinities of ligands to isolated binding sites, but preserving accuracy is essential. This chapter describes a step-by-step approach to multiple methods for identifying candidate sites and quantifying binding affinities and also discusses limitations and common pitfalls.

A Novel Bifunctional Alkylphenol Anesthetic Allows Characterization of γ-Aminobutyric Acid, Type A (GABAA), Receptor Subunit Binding Selectivity in Synaptosomes.

Propofol, an intravenous anesthetic, is a positive modulator of the GABAA receptor, but the mechanistic details, including the relevant binding sites and alternative targets, remain disputed. Here we undertook an in-depth study of alkylphenol-based anesthetic binding to synaptic membranes. We designed, synthesized, and characterized a chemically active alkylphenol anesthetic (2-((prop-2-yn-1-yloxy)methyl)-5-(3-(trifluoromethyl)-3H-diazirin-3-yl)phenol, AziPm-click (1)), for affinity-based protein profiling (ABPP) of propofol-binding proteins in their native state within mouse synaptosomes.

Role of the Fourth Transmembrane α Helix in the Allosteric Modulation of Pentameric Ligand-Gated Ion Channels.

The gating of pentameric ligand-gated ion channels is sensitive to a variety of allosteric modulators that act on structures peripheral to those involved in the allosteric pathway leading from the agonist site to the channel gate. One such structure, the lipid-exposed transmembrane α helix, M4, is the target of lipids, neurosteroids, and disease-causing mutations. Here we show that M4 interactions with the adjacent transmembrane α helices, M1 and M3, modulate pLGIC function.

Pentameric Ligand-gated Ion Channels : Insights from Computation.

Pentameric ligand-gated ion channels (pLGICs) conduct upon the binding of an agonist and are fundamental to neurotransmission. New insights into the complex mechanisms underlying pLGIC gating, ion selectivity, and modulation have recently been gained via a series of crystal structures in prokaryotes and , as well as computational studies relying on these structures. Here we review contributions from a variety of computational approaches, including normal mode analysis, automated docking, and fully atomistic molecular dynamics simulation.

A predicted binding site for cholesterol on the GABAA receptor.

Modulation of the GABA type A receptor (GABAAR) function by cholesterol and other steroids is documented at the functional level, yet its structural basis is largely unknown. Current data on structurally related modulators suggest that cholesterol binds to subunit interfaces between transmembrane domains of the GABAAR. We construct homology models of a human GABAAR based on the structure of the glutamate-gated chloride channel GluCl of Caenorhabditis elegans.