Exploration of Catalytic Selectivity for Aminotransferase (BtrR) Based on Multiple Molecular Dynamics Simulations

Abstract

The aminotransferase from Bacillus circulans (BtrR), which is involved in the biosynthesis of butirosin, catalyzes the pyridoxal phosphate (PLP)-dependent transamination reaction to convert valienone to β-valienamine (a new β-glycosidase inhibitor for the treatment of lysosomal storage diseases) with an optical purity enantiomeric excess value. To explore the stereoselective mechanism of valienamine generated by BtrR, multiple molecular dynamics (MD) simulations were performed for the BtrR/PLP/valienamine and BtrR/PLP/β-valienamine complexes. The theoretical results showed that β-valienamine could make BtrR more stable and dense than valienamine. β-valienamine could increase the hydrogen bond probability and decrease the binding free energy between coenzyme PLP and BtrR by regulating the protein structure of BtrR, which was conducive to the catalytic reaction. β-valienamine maintained the formation of cation-p interactions between basic and aromatic amino acids in BtrR, thus enhancing its stability and catalytic activity. In addition, CAVER 3.0 analysis revealed that β-valienamine could make the tunnel of BtrR wider and straight, which was propitious to the removal of products from BtrR. Steered MD simulation results showed that valienamine interacted with more residues in the tunnel during dissociation compared with β-valienamine, resulting in the need for a stronger force to be acquired from BtrR. Taken together, BtrR was more inclined to catalyze the substrates to form β-valienamine, either from the point of view of the catalytic reaction or product removal.

The Protection of Crocin Against Ulcerative Colitis and Colorectal Cancer via Suppression of NF-κB-Mediated Inflammation

“…The 3D structure of crocin was optimized by Gaussian 09 software (Ali et al, 2020) at 6-31G* set (Ye et al, 2020). And then crocin was docked to NF-κB (the 3D structure of NF-κB was built by Swiss model software 1 ) using AutoDock 4.2 software (Liu et al, 2019;Umesh et al, 2020). The current version of AutoDock, using the lamarckian genetic algorithm and empirical free energy scoring function, typically will provide reproducible docking results for ligands with approximately 10 flexible bonds.…”

Probing the Molecular Basis of Cofactor Affinity and Conformational Dynamics of Mycobacterium tuberculosis Elongation Factor Tu: An Integrated Approach Employing Steered Molecular Dynamics and Umbrella Sampling Simulations

“…The ligands were pulled at four different pull rates, i.e., 0.001, 0.0005, 0.0002, and 0.0001 nm/ps, and pulling simulations were performed over the course of 3, 6, 15, and 30 ns, respectively, by using a spring constant of 1000 kJ mol –1 nm –2 . The application of both slower and faster pulling rates resulted in the production of nearly similar force vs time curves and identical trajectories, but still, the slowest pulling rate (0.0001 nm/ps) was applied to all three systems for further study to avoid any artifacts and preserve the reliability of the results. − The snapshots obtained from the SMD trajectory were further used to generate the starting configurations for the umbrella sampling − windows. An asymmetric distribution of sampling windows was used such that the window spacing was 0.1 nm for a few initial nanometers of COM separation and 0.2 nm for the remaining COM separation .…”

How Different Substitution Positions of F, Cl Atoms in Benzene Ring of 5-Methylpyrimidine Pyridine Derivatives Affect the Inhibition Ability of EGFRL858R/T790M/C797S Inhibitors: A Molecular Dynamics Simulation Study

“…K745@NZ-L762@OE2 5. To investigate the interaction between the substrate and the active site, bottleneck residues were obtained by analyzing the molecular dynamics simulation trajectory through Channel Extraction and Visualization (CHEXVIS) [50][51][52], which revealed the structural details of the tunnel [53,54]. CHEXVIS was used to analyze 2500 snapshots from 100 ns molecular dynamics simulation of EGFR TM .…”