Two statins and cromolyn as possible drugs against the cytotoxicity of Aß(31-35) and Aß(25-35) peptides: a comparative study by advanced computer simulation methods.

In this work, possible effective mechanisms of cromolyn, atorvastatin and lovastatin on the cytotoxicity of Aß(31-35) and Aß(25-35) peptides were investigated by classical molecular dynamics and well-tempered metadynamics simulations. The results demonstrate that all the drugs affect the behavior of the peptides, such as their ability to aggregate, and alter their secondary structures and their affinity to a particular drug. Our findings from the computed properties suggest that the best drug candidate is lovastatin. This medicine inhibits peptide aggregation, adsorbs the peptides on the surface of the drug clusters, changes the secondary structure and binds to MET35, which has been seen as the reason for the toxicity of the studied peptide sequences. Moreover, lovastatin is the drug which previously has demonstrated the strongest ability to penetrate the blood-brain barrier and makes lovastatin the most promising medicine among the three investigated drugs. Atorvastatin is also seen as a potential candidate if its penetration through the blood-brain barrier could be improved. Otherwise, its properties are even better than the ones demonstrated by lovastatin. Cromolyn appears to be less interesting as an anti-aggregant from the computational data, in comparison to the two statins.

Component of Cannabis, Cannabidiol, as a Possible Drug against the Cytotoxicity of Aß(31-35) and Aß(25-35) Peptides: An Investigation by Molecular Dynamics and Well-Tempered Metadynamics Simulations.

In this work cannabidiol (CBD) was investigated as a possible drug against the cytotoxicity of Aß(31-35) and Aß(25-35) peptides with the help of atomistic molecular dynamics (MD) and well-tempered metadynamics simulations. Four interrelated mechanisms of possible actions of CBD are proposed from our computations. This implies that one mechanism can be a cause or/and a consequence of another. CBD is able to decrease the aggregation of peptides at certain concentrations of compounds in water. This particular action is more prominent for Aß(25-35), since originally Aß(31-35) did not exhibit aggregation properties in aqueous solutions. Interactions of CBD with the peptides affect secondary structures of the latter ones. Clusters of CBD are seen as possible adsorbents of Aß(31-35) and Aß(25-35) since peptides are tending to aggregate around them. And last but not least, CBD exhibits binding to MET35. All four mechanisms of actions can possibly inhibit the Aß-cytotoxicity as discussed in this paper. Moreover, the amount of water also played a role in peptide clustering: with a growing concentration of peptides in water without a drug, the aggregation of both Aß(31-35) and Aß(25-35) increased. The number of hydrogen bonds between peptides and water was significantly higher for simulations with Aß(25-35) at the higher concentration of peptides, while for Aß(31-35) that difference was rather insignificant. The presence of CBD did not substantially affect the number of hydrogen bonds in the simulated systems.

Exploring the potential energy surface of retinal, a comparison of the performance of different methods.

The ground state structure of retinal has been investigated. We found that DFT and CASSCF produce different results for the bond length alternation in a model system of retinal. Quantum mechanics/molecular mechanics calculations including the closest surrounding amino acids have been performed, using DFT and CASSCF to calculate the structure of retinal in the protein cavity. The planarity of the retinal molecule is affected by the surrounding protein. DFT and CASSCF produce different twist angles. The difference between CASSCF and DFT appears to be related to the positively charged nitrogen of the Schiff base, which leads to different pi-bond orders produced by the two methods.

Primary photoprocess in vision: minimal motion to reach the photo- and bathorhodopsin intermediates.

According to time-resolved spectroscopic measurements, the initial step of the photoreaction of rhodopsin occurs with a time constant of approximately 200 fs. The whole or a part of the retinal molecule cannot move any significant distance in such a short time. In this paper, we propose instead a minimal motion that accomplishes the important task of guiding the molecule to a configuration where it can decay to the ground-state surface, with a minimal loss of strain energy. This motion is proposed to involve a -90 degrees twisting of the C11=C12 double bond and a simultaneous twisting around two other double bonds in retinal to minimize the geometrical changes along the reaction path. The ONIOM method (complete active space self-consistent field for retinal and AMBER for the peptides) is used in a chromophore-cavity model to elucidate and confirm important features of the mechanism. The potential energy surface (PES) obtained according to the proposed mechanism show all of the characteristics of a fast photoreaction, meaning a downhill reaction path from the Franck-Condon point to an avoided crossing between S(1) and S(0). In this motion, only a few carbon and hydrogen atoms move more than 0.3 A, and the retinal structure is conserved in the protein cavity. We propose that the photorhodopsin intermediate is a retinal molecule formed on the excited-state PES. Bathorhodopsin, however, is a ground-state intermediate, still located inside the protein cavity.