Fig. 1: Computational design of a pan-nitazene biosensor.
From: Computational design of dynamic biosensors for emerging synthetic opioids
A Cartoon of the PYR-HAB chemically induced dimerization mechanism. B The structural definition of the transduction mechanism for PYR1 biosensors. The ligand shown as orange sticks is abscisic acid, the original PYR1 ligand. Red and white spheres show the bound water molecule oxygen and hydrogens, respectively. Black dashes represent polar interactions between the bound water and other atoms. C Structure of the nitazene central 2-benzyl benzimidazole with locations for possible substitutions color-coded. D Functional groups of nitazene derivatives organized by substitution position and contribution to molecular potency. The sign shows the direction of effect on potency (negative values are weaker potency), and the magnitude (logEC50) reflects contribution strength. Values are regression model coefficients from one-hot encoded functional group identities at each position. The R1 groups of isotonitazene and its less-potent metabolic product 4-hydroxy nitazene are labeled, as well as the common tertiary amine at R3 shared by both molecules. E Overview of the computational design process. Temperature replica exchange MD (TREMD) is used to identify highly prevalent solution populated ligand conformers. These conformers are aligned to key molecular features preserving the PYR1 transduction mechanism, and sequences are designed to each pose. This process is iterated over conformer and alignment perturbations and filtered to identify sets of sequences. A library is encoded using position-specific and local residue preferences.
