A multiscale study on photophysical properties of a novel fluorescent probe for imaging amyloid-β in Alzheimer's disease

Detection of amyloid-β deposition in the brain region is of significant importance for early diagnosis of Alzheimer's disease (AD). In the last few decades, the fluorescent imaging technique has been considered an effective tool for detecting amyloid-β plaques due to its safety, sensitivity, and operability. Thus, numerous fluorescent probes for amyloid-β have been developed. The design of a probe with high selectivity and improved sensing performance requires knowledge about the potential binding sites for the probe in amyloid-β and local microstructure of the probe in different sites. In this study, amyloid-β-specific photophysical properties of a novel fluorescent probe (cis-PAD-1) are theoretically investigated by using multiscale simulations, including molecular docking and quantum mechanics/molecular mechanics calculations. Binding profile of cis-PAD-1 in amyloid-β has been simulated, and binding affinity of the probe in various sites is calculated. An excited-state property study on cis-PAD-1 illustrates that the probe shows remarkable fluorescence enhancement in amyloid-β due to the influence of the microenvironment, which is consistent with the experimental observation. Most importantly, two-photon absorption cross section of the probe is greatly increased in the near-infrared region when targeting with amyloid-β owing to the enhanced transition dipole moment. Therefore, one can propose the usage of cis-PAD-1 as an excellent candidate in two-photon fluorescent imaging for amyloid-β. The detailed investigations provide information on the development and design strategy of a new fluorescent probe for amyloid-β imaging in AD.     

Preorganization and reorganization as related factors in enzyme catalysis: the chorismate mutase case

In this paper a deeper insight into the chorismate-to prephenate-rearrangement, catalyzed by Bacillus subtilis chorismate mutase, is provided by means of a combination of statistical quantum mechanics/molecular mechanics simulation methods and hybrid potential energy surface exploration techniques. The main aim of this work is to present an estimation of the preorganization and reorganization terms of the enzyme catalytic rate enhancement. To analyze the first of these, we have studied different conformational equilibria of chorismate in aqueous solution and in the enzyme active site. Our conclusion is that chorismate mutase preferentially binds the reactive conformer of the substrate--that presenting a structure similar to the transition state of the reaction to be catalyzed--with shorter distances between the carbon atoms to be bonded and more diaxial character. With respect to the reorganization effect, an energy decomposition analysis of the potential energies of the reactive reactant and of the reaction transition state in aqueous solution and in the enzyme shows that the enzyme structure is better adapted to the transition structure. This means not only a more negative electrostatic interaction energy with the transition state but also a low enzyme deformation contribution to the energy barrier. Our calculations reveal that the structure of the enzyme is responsible for stabilizing the transition state structure of the reaction, with concomitant selection of the reactive form of the reactants. This is, the same enzymatic pattern that stabilizes the transition structure also promotes those reactant structures closer to the transition structure (i.e., the reactive reactants). In fact, both reorganization and preorganization effects have to be considered as the two faces of the same coin, having a common origin in the effect of the enzyme structure on the energy surface of the substrate.