Acetylcholinesterase (AChE) is an important hydrolase in cholinergic synapses and a candidate target in the treatment of Alzheimer's disease. The lithium treatment widely used in neurological disorders can alter the AChE activity, yet the underlying mechanism of how the ion species regulate the enzymatic activity remains unclear. In this work, we performed combined quantum mechanics/molecular mechanics (QM/MM) and molecular dynamics (MD) simulations and well-tempered metadynamics to understand the modulation of human AChE (hAChE) activity using three alkali metal ions (Li+, Na+, and K+) in different concentrations. Our simulations show that the binding affinity and catalytic activity are affected by different ion species through allosteric ion coordination geometries on the hAChE complex and distant electrostatic screening effect. A Li+ cluster involving D330, E393, and D397 residues and three Li+ ions was found to be highly conserved and can be critical to the enzyme activity. Binding energy calculations indicate that the electrostatic screening from allosterically bound cations can affect the key residues at the catalytic site and active-site gorge, including E199. Furthermore, an increase in ion concentration can lead to lower reactivity, especially for Li+ ions, which exhibit more cation-hAChE contacts than Na+ and K+. The selective ion binding and their preferred modulation on hAChE are highly related to ion species. This work provides a molecular perspective on selective modulation by different ion species of the enzyme catalytic processes.
Acetylcholinesterase , Metals, Alkali , Humans , Acetylcholinesterase/chemistry , Metals, Alkali/chemistry , Lithium/chemistry , Sodium/chemistry , Cations
To expand the capabilities of reactive force field (ReaxFF) in simulations of biological processes involving glucose, in this work, using Metropolis Monte Carlo algorithm, new ReaxFF parameters for glucose have been developed to better describe the properties of glucose in water during molecular dynamics (MD) simulations. With the newly trained ReaxFF, the mutarotation of glucose in water can be better described, as suggested by our metadynamics simulations. In addition, the newly trained ReaxFF can better describe the distributions of the three stable conformers along the key dihedral angle of α-anomer and ß-anomer. With better descriptions of hydration around glucose, the Raman and Raman optical activity spectra can be more accurately calculated. In addition, the infrared spectra obtained from simulations with the new glucose ReaxFF are more accurate than those obtained with the original ReaxFF. We note that although our trained ReaxFF performs better than the original ReaxFF, it is not generally applicable to all carbohydrates, which require further parametrization. We also find that the absence of explicit water molecules in the training sets may lead to inaccurate descriptions of water-water interactions around the glucose, implicating that it is necessary to optimize the water ReaxFF parameters together with the target molecule. The improved ReaxFF makes it possible to explore interesting biological processes involving glucose more accurately and efficiently.
Identification and characterization of materials used in cultural heritage and conservation can provide important information for dating, authentication and deteriorating situation in general. How to extract useful information from these materials in-situ is one of the main concerns. Application of mobile Raman spectroscopy for this purpose has great attentions for scientists and conservators. The present paper aims to investigate the mobile Raman spectroscopy in studying the effect of UV light on the deterioration of silk, seal ink and Chinese traditional colorants such as kermes, vermillion and zhubiao, which is commonly appeared on painted works of art, and the silk sample is also often used as an consolidant for repairing destroyed textile objects. Spectra were recorded from predefined regions on the samples before and after ultraviolet radiation with 360 nm wavelength and 0.68 W x m(-2) intensity. The result revealed obvious effects of ultraviolet radiation on the materials simulated in this research. The original kind of seal ink has been clearly identified. The changes in spectra of all samples with and without UV radiation were further distinguished and studied. The result will assist for scientists and conservators to determine the safe treatments and suitable environmental condition for storage, display and transport. The result will also help for studying mechanism of deterioration of museum objects influenced by environmental factors. The mobile Raman spectroscopy showed a suitable and convenient means for in-situ non-destructive detection and study of deterioration in practical conditions.
